Continuous carbonylation processes

ABSTRACT

Provided are processes for monitoring and maintaining continuous carbonylation of epoxides or lactones. Processes include measuring parameters affecting the rate of the carbonylation reaction and adding supplemental replacement catalyst replacement components to maintain a constant rate of carbonylation.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Phase Patent Application ofPCT/US2016/017875, filed Feb. 12, 2016, which claims priority to and thebenefit of U.S. Provisional Patent Application No. 62/116,089, filedFeb. 13, 2015, each of which is incorporated herein by reference in itsentirety.

FIELD

The present disclosure relates generally to a carbonylation reaction,and more specifically to the continuous carbonylation of an epoxide orlactone feedstock.

BACKGROUND

Bimetallic complexes containing a Lewis acid in combination with metalcarbonyl are highly active catalysts for the ring-expandingcarbonylation of strained heterocycles, including epoxides, aziridines,oxetanes and lactones. In particular, such bimetallic catalystscomprising a cationic aluminum complex as a Lewis-acidic component and acarbonyl cobaltate anion are useful for the mono- and bis-carbonylationof epoxides to form beta-lactones and succinic anhydrides respectively(Rowley et al., J. Am. Chem. Soc., 2007, 129, 4948-4960).

Continuous production of these beta-lactones and succinic anhydrides ispossible by the continuous addition of epoxide and carbon monoxidefeedstocks, and the continuous removal of the beta-lactone or succinicanhydride products. However, the carbonylation catalysts used for thesereactions have a limited effective lifespan, and accordingly, thecontinuous production of carbonylation products slows down over time orceases entirely once the active catalyst species is no longer present tocatalyze the reaction. These active catalysts are expensive, so theaddition of a whole new amount of active catalyst is not economicallypreferable.

Furthermore, many of the active catalysts are air sensitive and it isundesirable to have to produce and handle them in a separate step priorto adding them to the continuous carbonylation reactor. Such a separatestep can be problematic at commercial production volumes. As such, thereremains a need for methods of maintaining effective amounts ofcarbonylation catalysts in a continuous carbonylation reactor that arepractical and efficient for large-scale use.

BRIEF SUMMARY

In one aspect, provided is a process for continuous carbonylation of anepoxide or lactone feedstock, comprising:

reacting an epoxide or lactone feedstock with carbon monoxide in thepresence of a catalyst comprising a Lewis acid and a metal carbonyl in acarbonylation reaction vessel;

measuring one or more parameters selected from the group consisting of:

-   -   i) a concentration of the Lewis acid, or a decomposition product        thereof, within the carbonylation reaction vessel;    -   ii) a concentration of the Lewis acid, or a decomposition        product thereof, in a product stream downstream from the        carbonylation reaction vessel;    -   iii) a concentration of the metal carbonyl, or a decomposition        product thereof, within the carbonylation reaction vessel;    -   iv) a concentration of the metal carbonyl, or a decomposition        product thereof, in a product stream downstream from the        carbonylation reaction vessel; and    -   v) a rate of the carbonylation reaction;

comparing the measured value of the one or more parameters topredetermined reference values for the one or more parameters; and

where the measured value of any one of parameters i), iii), or v) isless than the reference value, or where the measured value of any one ofparameters ii) or iv) is greater than the reference value, introducingto the carbonylation reaction vessel a catalyst replacement componentwhich is different from the catalyst and comprises a species selectedfrom the group consisting of the Lewis acid, a precursor to the Lewisacid, the metal carbonyl, and a precursor to the metal carbonyl.

In another aspect, provided is a process for continuous carbonylation ofan epoxide or lactone feedstock, comprising:

continuously reacting an epoxide or lactone feedstock with carbonmonoxide in the presence of a carbonylation catalyst in a carbonylationreaction vessel,

-   -   wherein the carbonylation catalyst comprises a Lewis acid and a        metal carbonyl, and    -   wherein at a start time of the process, the carbonylation        reaction vessel contains an initial concentration of the Lewis        acid and an initial concentration of the metal carbonyl; and

adding to the carbonylation reaction vessel, at a time after the starttime of the process, a catalyst replacement component which is differentfrom the catalyst,

-   -   wherein the catalyst replacement component comprises the Lewis        acid, a precursor to the Lewis acid, the metal carbonyl, and a        precursor to the metal carbonyl.

In some variations of the foregoing aspect, a rate or time of additionof the catalyst replacement component is based on a rate of depletion ofone or both of the Lewis acid and the metal carbonyl in thecarbonylation reaction vessel.

In another aspect, provided is a process for continuous carbonylation ofan epoxide or lactone feedstock, comprising:

reacting an epoxide or lactone feedstock with carbon monoxide in thepresence of a catalyst in a carbonylation reaction vessel, wherein thecatalyst comprises a Lewis acid and a metal carbonyl; and

continuously or intermittently introducing to the carbonylation reactionvessel a catalyst replacement component which is different from thecatalyst, wherein the catalyst replacement component comprises a speciesselected from the group consisting of the Lewis acid, a precursor to theLewis acid, the metal carbonyl, and a precursor to the metal carbonyl.

In some embodiments, the Lewis acids, decomposition products of Lewisacids, precursors to the Lewis acids, metal carbonyls, decompositionproducts of metal carbonyls, and precursors to the metal carbonylsinclude those described in classes and subclasses herein.

Definitions

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, andspecific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in OrganicChemistry, Thomas Sorrell, University Science Books, Sausalito, 1999;Smith and March March's Advanced Organic Chemistry, 5^(th) Edition, JohnWiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; Carruthers, SomeModern Methods of Organic Synthesis, 3^(rd) Edition, CambridgeUniversity Press, Cambridge, 1987.

The terms “halo” and “halogen” as used herein refer to an atom selectedfrom fluorine (fluoro, —F), chlorine (chloro, —Cl), bromine (bromo,—Br), and iodine (iodo, —I).

The term “aliphatic” or “aliphatic group”, as used herein, denotes ahydrocarbon moiety that may be straight-chain (i.e., unbranched),branched, or cyclic (including fused, bridging, and spiro-fusedpolycyclic) and may be completely saturated or may contain one or moreunits of unsaturation, but which is not aromatic. In some variations,the aliphatic group is unbranched or branched. In other variations, thealiphatic group is cyclic. Unless otherwise specified, in somevariations, aliphatic groups contain 1-30 carbon atoms. In someembodiments, aliphatic groups contain 1-12 carbon atoms. In someembodiments, aliphatic groups contain 1-8 carbon atoms. In someembodiments, aliphatic groups contain 1-6 carbon atoms. In someembodiments, aliphatic groups contain 1-5 carbon atoms, in someembodiments, aliphatic groups contain 1-4 carbon atoms, in yet otherembodiments aliphatic groups contain 1-3 carbon atoms, and in yet otherembodiments aliphatic groups contain 1-2 carbon atoms. Suitablealiphatic groups include, for example, linear or branched, alkyl,alkenyl, and alkynyl groups, and hybrids thereof such as(cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

The term “heteroaliphatic,” as used herein, refers to aliphatic groupswherein one or more carbon atoms are independently replaced by one ormore atoms selected from the group consisting of oxygen, sulfur,nitrogen, phosphorus, or boron. In some embodiments, one or two carbonatoms are independently replaced by one or more of oxygen, sulfur,nitrogen, or phosphorus. Heteroaliphatic groups may be substituted orunsubstituted, branched or unbranched, cyclic or acyclic, and include“heterocycle,” “heterocyclyl,” “heterocycloaliphatic,” or “heterocyclic”groups. In some variations, the heteroaliphatic group is branched orunbranched. In other variations, the heteroaliphatic group is cyclic. Inyet other variations, the heteroaliphatic group is acyclic.

In some variations, the term “epoxide”, as used herein, refers to asubstituted or unsubstituted oxirane. Substituted oxiranes includemonosubstituted oxiranes, disubstituted oxiranes, trisubstitutedoxiranes, and tetrasubstituted oxiranes. Such epoxides may be furtheroptionally substituted as defined herein. In some embodiments, epoxidescomprise a single oxirane moiety. In some embodiments, epoxides comprisetwo or more oxirane moieties.

In some variations, the term “glycidyl”, as used herein, refers to anoxirane substituted with a hydroxyl methyl group or a derivativethereof. In other variations, the term glycidyl as used herein is meantto include moieties having additional substitution on one or more of thecarbon atoms of the oxirane ring or on the methylene group of thehydroxymethyl moiety, examples of such substitution may include, forexample, alkyl groups, halogen atoms, and aryl groups. The termsglycidyl ester, glycidyl acrylate, and glydidyl ether denotesubstitution at the oxygen atom of the above-mentioned hydroxymethylgroup. For example, the oxygen atom is bonded to an acyl group, anacrylate group, or an alkyl group respectively.

The term “acrylate” or “acrylates” as used herein refer to any acylgroup having a vinyl group adjacent to the acyl carbonyl. The termsencompass mono-, di- and tri-substituted vinyl groups. Acrylates mayinclude, for example, acrylate, methacrylate, ethacrylate, cinnamate(3-phenylacrylate), crotonate, tiglate, and senecioate.

The terms “crude acrylic acid” and “glacial acrylic acid”, as usedherein, describe acrylic acid of relatively low and high purity,respectively. Crude acrylic acid (also called technical grade acrylicacid) has a typical minimum overall purity level of 94% and can be usedto make acrylic esters for paint, adhesive, textile, paper, leather,fiber, and plastic additive applications. Glacial acrylic acid has atypical overall purity level ranging from 98% to 99.99% and can be usedto make polyacrylic acid for superabsorbent polymers (SAPs) indisposable diapers, training pants, adult incontinence undergarments andsanitary napkins. Polyacrylic acid (PAA) is also used in compositionsfor paper and water treatment, and in detergent co-builder applications.In some variations, acrylic acid has a purity of at least 98%, at least98.5%, at least 99%, at least 99.1%, at least 99.2%, at least 99.3%, atleast 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least99.8%, or at least 99.9%; or between 99% and 99.95%, between 99.5% and99.95%, between 99.6% and 99.95%, between 99.7% and 99.95%, or between99.8% and 99.95%.

Suitable salts of PAA include metal salts, such those of any alkali(e.g., Na⁺, K⁺) cations, alkaline earth cations. In certain embodiments,the PAA salt is the Na⁺ salt, i.e., sodium PAA. In certain embodiments,the salt is the K⁺ salt, i.e., potassium PAA.

Impurities in glacial acrylic acid are reduced to an extent possible tofacilitate a high-degree of polymerization to acrylic acid polymers(PAA) and avoid adverse effects from side products in end applications.For example, aldehyde impurities in acrylic acid hinder polymerizationand may discolor the polymerized acrylic acid. Maleic anhydrideimpurities form undesirable copolymers which may be detrimental topolymer properties. Carboxylic acids, e.g., saturated carboxylic acidsthat do not participate in the polymerization, can affect the final odorof PAA or SAP-containing products and/or detract from their use. Forexample, foul odors may emanate from SAP that contains acetic acid orpropionic acid and skin irritation may result from SAP that containsformic acid.

The reduction or removal of impurities from petroleum-based acrylic acidis costly, whether to produce petroleum-based crude acrylic acid orpetroleum-based glacial acrylic acid. Such costly multistagedistillations and/or extraction and/or crystallizations steps aregenerally employed (e.g., as described in U.S. Pat. Nos. 5,705,688 and6,541,665).

The term “polymer”, as used herein, refers to a molecule comprisingmultiple repeating units. In some variations, the polymer is a moleculeof high relative molecular mass, the structure of which comprises themultiple repetition of units derived, actually or conceptually, frommolecules of low relative molecular mass. In some embodiments, a polymeris comprised of only one monomer species (e.g., polyethylene oxide). Insome embodiments, the polymer may be a copolymer, terpolymer,heteropolymer, block copolymer, or tapered heteropolymer of one or moreepoxides. In one variation, the polymer may be a copolymer, terpolymer,heteropolymer, block copolymer, or tapered heteropolymer of two or moremonomers.

The term “unsaturated”, as used herein, means that a moiety has one ormore double or triple bonds.

The terms “cycloaliphatic”, “carbocycle”, or “carbocyclic”, used aloneor as part of a larger moiety, refer to a saturated or partiallyunsaturated cyclic aliphatic monocyclic, bicyclic, or polycyclic ringsystems, as described herein, having from 3 to 12 members, wherein thealiphatic ring system is optionally substituted as defined above anddescribed herein. Cycloaliphatic groups include, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl,cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, andcyclooctadienyl. In some embodiments, the cycloalkyl has 3-6 carbons.The terms “cycloaliphatic”, “carbocycle” or “carbocyclic” also includealiphatic rings that are fused to one or more aromatic or nonaromaticrings, such as decahydronaphthyl or tetrahydronaphthyl, where theradical or point of attachment is on the aliphatic ring. In someembodiments, a carbocyclic groups is bicyclic. In some embodiments, acarbocyclic group is tricyclic. In some embodiments, a carbocyclic groupis polycyclic.

The term “alkyl,” as used herein, refers to a saturated hydrocarbonradical. In some variations, the alkyl group is a saturated, straight-or branched-chain hydrocarbon radicals derived from an aliphatic moietycontaining between one and six carbon atoms by removal of a singlehydrogen atom. Unless otherwise specified, in some variations, alkylgroups contain 1-12 carbon atoms. In some embodiments, alkyl groupscontain 1-8 carbon atoms. In some embodiments, alkyl groups contain 1-6carbon atoms. In some embodiments, alkyl groups contain 1-5 carbonatoms, in some embodiments, alkyl groups contain 1-4 carbon atoms, inyet other embodiments alkyl groups contain 1-3 carbon atoms, and in yetother embodiments alkyl groups contain 1-2 carbon atoms. Alkyl radicalsmay include, for example to, methyl, ethyl, n-propyl, isopropyl,n-butyl, iso-butyl, sec-butyl, sec-pentyl, iso-pentyl, tert-butyl,n-pentyl, neopentyl, n-hexyl, sec-hexyl, n-heptyl, n-octyl, n-decyl,n-undecyl, and dodecyl.

The term “alkenyl,” as used herein, denotes a monovalent group having atleast one carbon-carbon double bond. In some variations, the alkenylgroup is a monovalent group derived from a straight- or branched-chainaliphatic moiety having at least one carbon-carbon double bond by theremoval of a single hydrogen atom. Unless otherwise specified, in somevariations, alkenyl groups contain 2-12 carbon atoms. In someembodiments, alkenyl groups contain 2-8 carbon atoms. In someembodiments, alkenyl groups contain 2-6 carbon atoms. In someembodiments, alkenyl groups contain 2-5 carbon atoms, in someembodiments, alkenyl groups contain 2-4 carbon atoms, in yet otherembodiments alkenyl groups contain 2-3 carbon atoms, and in yet otherembodiments alkenyl groups contain 2 carbon atoms. Alkenyl groupsinclude, for example, ethenyl, propenyl, butenyl, and1-methyl-2-buten-1-yl.

The term “alkynyl,” as used herein, refers to a monovalent group havingat least one carbon-carbon triple bond. In some variations, the alkynylgroup is a monovalent group derived from a straight- or branched-chainaliphatic moiety having at least one carbon-carbon triple bond by theremoval of a single hydrogen atom. Unless otherwise specified, in somevariations, alkynyl groups contain 2-12 carbon atoms. In someembodiments, alkynyl groups contain 2-8 carbon atoms. In someembodiments, alkynyl groups contain 2-6 carbon atoms. In someembodiments, alkynyl groups contain 2-5 carbon atoms, in someembodiments, alkynyl groups contain 2-4 carbon atoms, in yet otherembodiments alkynyl groups contain 2-3 carbon atoms, and in yet otherembodiments alkynyl groups contain 2 carbon atoms. Representativealkynyl groups include, for example ethynyl, 2-propynyl (propargyl), and1-propynyl.

The term “carbocycle” and “carbocyclic ring” as used herein, refers tomonocyclic and polycyclic moieties wherein the rings contain only carbonatoms. Unless otherwise specified, carbocycles may be saturated,partially unsaturated or aromatic, and contain 3 to 20 carbon atoms.Representative carbocyles include, for example, cyclopropane,cyclobutane, cyclopentane, cyclohexane, bicyclo[2,2,1]heptane,norbornene, phenyl, cyclohexene, naphthalene, and spiro[4.5]decane.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic andpolycyclic ring systems having a total of five to 20 ring members,wherein at least one ring in the system is aromatic and wherein eachring in the system contains three to twelve ring members. The term“aryl” may be used interchangeably with the term “aryl ring”. In someembodiments, “aryl” refers to an aromatic ring system which includes,for example, phenyl, naphthyl, and anthracyl, which may bear one or moresubstituents. Also included within the scope of the term “aryl”, as itis used herein, is a group in which an aromatic ring is fused to one ormore additional rings, such as benzofuranyl, indanyl, phthalimidyl,naphthimidyl, phenanthridinyl, and tetrahydronaphthyl.

The terms “heteroaryl” and “heteroar-”, used alone or as part of alarger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer togroups having 5 to 14 ring atoms, preferably 5, 6, 9 or 10 ring atoms;having 6, 10, or 14 pi (π) electrons shared in a cyclic array; andhaving, in addition to carbon atoms, from one to five heteroatoms. Theterm “heteroatom” refers to nitrogen, oxygen, or sulfur, and includesany oxidized form of nitrogen or sulfur, and any quaternized form of abasic nitrogen. Heteroaryl groups include, for example, thienyl,furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl,thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl,purinyl, naphthyridinyl, benzofuranyl and pteridinyl. The terms“heteroaryl” and “heteroar-”, as used herein, also include groups inwhich a heteroaromatic ring is fused to one or more aryl,cycloaliphatic, or heterocyclyl rings, where the radical or point ofattachment is on the heteroaromatic ring. Examples include indolyl,isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl,benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl,phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl,acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, andpyrido[2,3-b]-1,4-oxazin-3(4H)-one. A heteroaryl group may be monocyclicor bicyclic. The term “heteroaryl” may be used interchangeably with theterms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”, any ofwhich terms include rings that are optionally substituted. The term“heteroaralkyl” refers to an alkyl group substituted by a heteroaryl,wherein the alkyl and heteroaryl portions independently are optionallysubstituted.

As used herein, the terms “heterocycle”, “heterocyclyl”, “heterocyclicradical”, and “heterocyclic ring” are used interchangeably and may besaturated or partially unsaturated, and have, in addition to carbonatoms, one or more, preferably one to four, heteroatoms, as definedabove. In some variations, the heterocyclic group is a stable 5- to7-membered monocyclic or 7- to 14-membered bicyclic heterocyclic moietythat is either saturated or partially unsaturated, and having, inaddition to carbon atoms, one or more, preferably one to four,heteroatoms, as defined above. When used in reference to a ring atom ofa heterocycle, the term “nitrogen” includes a substituted nitrogen. Asan example, in a saturated or partially unsaturated ring having 0-3heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen maybe N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or ⁺NR(as in N-substituted pyrrolidinyl).

A heterocyclic ring can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted. Examples of such saturatedor partially unsaturated heterocyclic radicals include, for example,tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl,piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. Theterms “heterocycle”, “heterocyclyl”, “heterocyclyl ring”, “heterocyclicgroup”, “heterocyclic moiety”, and “heterocyclic radical”, are usedinterchangeably herein, and also include groups in which a heterocyclylring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings,such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, ortetrahydroquinolinyl, where the radical or point of attachment is on theheterocyclyl ring. A heterocyclyl group may be mono- or bicyclic. Theterm “heterocyclylalkyl” refers to an alkyl group substituted by aheterocyclyl, wherein the alkyl and heterocyclyl portions independentlyare optionally substituted.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond. The term “partiallyunsaturated” is intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aryl or heteroarylmoieties, as herein defined.

As described herein, compounds described herein may contain “optionallysubstituted” moieties. In general, the term “substituted”, whetherpreceded by the term “optionally” or not, means that one or morehydrogens of the designated moiety are replaced with a suitablesubstituent. Unless otherwise indicated, an “optionally substituted”group may have a suitable substituent at each substitutable position ofthe group, and when more than one position in any given structure may besubstituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned are preferably thosethat result in the formation of stable or chemically feasible compounds.The term “stable”, as used herein, refers to compounds that are notsubstantially altered when subjected to conditions to allow for theirproduction, detection, and, in some embodiments, their recovery,purification, and use for one or more of the purposes disclosed herein.

In some chemical structures herein, substituents are shown attached to abond which crosses a bond in a ring of the depicted molecule. This meansthat one or more of the substituents may be attached to the ring at anyavailable position (usually in place of a hydrogen atom of the parentstructure). In cases where an atom of a ring so substituted has twosubstitutable positions, two groups may be present on the same ringatom. When more than one substituent is present, each is definedindependently of the others, and each may have a different structure. Incases where the substituent shown crossing a bond of the ring is —R,this has the same meaning as if the ring were said to be “optionallysubstituted” as described in the preceding paragraph.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently halogen;—(CH₂)₀₋₄R^(∘); —(CH₂)₀₋₄OR^(∘); —O—(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄CH(OR^(∘))₂; —(CH₂)₀₋₄SR^(∘); —(CH₂)₀₋₄Ph, which may besubstituted with R^(∘); —(CH₂)₀₋₄O(CH₂)₀₋₁Ph which may be substitutedwith R^(∘); —CH═CHPh, which may be substituted with R^(∘); —NO₂; —CN;—N₃; —(CH₂)₀₋₄N(R^(∘))₂; —(CH₂)₀₋₄N(R^(∘))C(O)R^(∘); —N(R^(∘))C(S)R^(∘);—(CH₂)₀₋₄N(R^(∘)) C(O)NR^(∘) ₂; —N(R^(∘))C(S)NR^(∘) ₂;—(CH₂)₀₋₄N(R^(∘))C(O)OR^(∘); —N(R^(∘))N(R^(∘))C(O)R^(∘);—N(R^(∘))N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))N(R^(∘))C(O)OR^(∘);—(CH₂)₀₋₄C(O)R^(∘); —C(S)R^(∘); —(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄C(O)N(R^(∘))₂; —(CH₂)₀₋₄C(O)SR^(∘); —(CH₂)₀₋₄C(O)OSiR^(∘) ₃;—(CH₂)₀₋₄OC(O)R^(∘); —OC(O)(CH₂)₀₋₄SR^(∘), —SC(S)SR^(∘);—(CH₂)₀₋₄SC(O)R^(∘); —(CH₂)₀₋₄C(O)NR^(∘) ₂; —C(S)NR^(∘) ₂; —C(S)SR^(∘);—SC(S)SR^(∘), —(CH₂)₀₋₄OC(O)NR^(∘) ₂; —C(O)N(OR^(∘))R^(∘);—C(O)C(O)R^(∘); —C(O)CH₂C(O)R^(∘); —C(NOR^(∘))R^(∘); —(CH₂)₀₋₄SSR^(∘);—(CH₂)₀₋₄S(O)₂R⁰; —(CH₂)₀₋₄S(O)₂OR^(∘); —(CH₂)₀₋₄OS(O)₂R^(∘),—S(O)₂NR^(∘) ₂; —(CH₂)₀₋₄S(O)R^(∘); —N(R^(∘))S(O)₂NR^(∘) ₂;—N(R^(∘))S(O)₂R^(∘); —N(OR^(∘))R^(∘); —C(NH)NR^(∘) ₂; —P(O)₂R^(∘);—P(O)R^(∘) ₂; —OP(O)R^(∘) ₂; —OP(O)(OR^(∘))₂; SiR^(∘) ₃; —(C₁₋₄ straightor branched)alkylene)O—N(R^(∘))₂; or —(C₁₋₄ straight orbranched)alkylene)C(O)O—N(R^(∘))₂, wherein each R^(∘) may be substitutedas defined below and is independently hydrogen, C₁₋₈ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur, or, notwithstanding the definition above, twoindependent occurrences of R^(∘), taken together with their interveningatom(s), form a 3-12-membered saturated, partially unsaturated, or arylmono- or polycyclic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur, which may be substituted as definedbelow.

Suitable monovalent substituents on R^(∘) (or the ring formed by takingtwo independent occurrences of R^(∘) together with their interveningatoms), are independently halogen, —(CH₂)₀₋₂R^(●), -(haloR^(●)),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(●), —(CH₂)₀₋₂CH(OR^(●))₂; —O(haloR^(●)), —CN,—N₃, —(CH₂)₀₋₂C(O)R^(●), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(●),—(CH₂)₀₋₄C(O)N(R^(∘))₂; —(CH₂)₀₋₂SR^(●), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂,—(CH₂)₀₋₂NHR^(●), —(CH₂)₀₋₂NR^(●) ₂, —NO₂, —SiR^(●) ₃, —OSiR^(●) ₃,—C(O)SR^(●), —(C₁₋₄ straight or branched alkylene)C(O)OR^(●), or—SSR^(●) wherein each R^(●) is unsubstituted or where preceded by “halo”is substituted only with one or more halogens, and is independentlyselected from C₁₋₄ aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. Suitabledivalent substituents on a saturated carbon atom of R^(∘) include ═O and═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*₂))₂₋₃O—, or—S(C(R*₂))₂₋₃S—, wherein each independent occurrence of R* is selectedfrom hydrogen, C₁₋₆ aliphatic which may be substituted as defined below,or an unsubstituted 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur. Suitable divalent substituents that are bound tovicinal substitutable carbons of an “optionally substituted” groupinclude: —O(CR*₂)₂₋₃O—, wherein each independent occurrence of R* isselected from hydrogen, C₁₋₆ aliphatic which may be substituted asdefined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur.

Suitable substituents on the aliphatic group of R* include halogen,—R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN, —C(O)OH,—C(O)OR^(●), —NH₂, —NHR^(●), —NR^(●) ₂, or —NO₂, wherein each R^(●) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein eachR^(†) is independently hydrogen, C₁₋₆ aliphatic which may be substitutedas defined below, unsubstituted —OPh, or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(●), taken together with their intervening atom(s) form anunsubstituted 3-12-membered saturated, partially unsaturated, or arylmono- or bicyclic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur.

Suitable substituents on the aliphatic group of R^(†) are independentlyhalogen, —R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN,—C(O)OH, —C(O)OR^(●), —NH₂, —NHR^(●), —NR^(●) ₂, or —NO₂, wherein eachR^(●) is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur.

As used herein, the term “catalyst” refers to a substance the presenceof which increases the rate of a chemical reaction, while not beingconsumed or undergoing a permanent chemical change itself.

“Tetradentate” refers to ligands having four sites capable ofcoordinating to a single metal center.

As used herein, the term “about” preceding one or more numerical valuesmeans the numerical value ±5%. It should be understood that reference to“about” a value or parameter herein includes (and describes) embodimentsthat are directed to that value or parameter per se. For example,description referring to “about x” includes description of “x” per se.

DETAILED DESCRIPTION

Provided herein are carbonylation methods that employ a two-componentcatalyst system comprising a Lewis acid and a metal carbonyl. In someaspects, such methods are a continuous carbonylation process whereinepoxides and carbon monoxide are fed in, and carbonylation reactionproducts are continuously produced. The methods described herein solve aproblem associated with continuous carbonylation processes, whereby overthe course of time, one component of the two-component catalyst systemis depleted at a faster rate than the other. As both components of thetwo-component catalyst system are required to effect the carbonylationreaction, the overall carbonylation reaction rate decreases with thedecrease in concentration of the least plentiful component.

In some embodiments, particularly where the product stream is separatedfrom the carbonylation reaction vessel by a nanofiltration membrane, oneor both components of the catalyst have unexpectedly been observed topass through the nanofiltration membrane. This observation is unexpectedsince the nanofiltration membrane is specifically selected to retainboth components of the two-component catalyst, while allowing thecarbonylation reaction products to pass. In some embodiments, themethods described herein restore proper balance between the componentsof the two-component catalyst by supplementation with the depletedcatalyst components, in the form of catalyst replacement components.

In some embodiments, one or both of the components of the two-componentcatalyst are decomposed by exposure to trace quantities of oxygen,water, or other external contaminants, despite careful measures toexclude them. This results in decomposition products of the catalystpersisting in the carbonylation reaction vessel or passing into theproduct stream. In one embodiment, the decomposition products can becombined with catalyst replacement components to regenerate the activecatalyst components without the need to add entirely new portions ofcatalyst. In some embodiments, where the decomposition products persistin the carbonylation reaction vessel, the addition of the catalystreplacement components results in the in situ regeneration of the activetwo-component catalyst. In some embodiments, where the decompositionproducts pass into the product stream, they may be isolated from theproduct stream and combined with the catalyst replacement components(either in situ or ex situ) to regenerate the active two-componentcatalyst.

In some embodiments, one or both components of the catalyst passes intothe product stream, and one or both components are decomposed.

I. Process for Monitoring and Replacing Catalyst

In one aspect, provided is a process for continuous carbonylation of anepoxide or lactone feedstock, comprising:

reacting an epoxide or lactone feedstock with carbon monoxide in thepresence of a catalyst comprising a Lewis acid and a metal carbonyl in acarbonylation reaction vessel;

measuring one or more parameters selected from the group consisting of:

-   -   i) a concentration of the Lewis acid, or a decomposition product        thereof, within the carbonylation reaction vessel;    -   ii) a concentration of the Lewis acid, or a decomposition        product thereof, in a product stream downstream from the        carbonylation reaction vessel;    -   iii) a concentration of the metal carbonyl, or a decomposition        product thereof, within the carbonylation reaction vessel;    -   iv) a concentration of the metal carbonyl, or a decomposition        product thereof, in a product stream downstream from the        carbonylation reaction vessel; and    -   v) a rate of the carbonylation reaction;

comparing the measured value of the one or more parameters topredetermined reference values for the one or more parameters; and

where the measured value of any one of parameters i), iii), or v) isless than the reference value, or where the measured value of any one ofparameters ii) or iv) is greater than the reference value, introducingto the carbonylation reaction vessel a catalyst replacement componentwhich is different from the catalyst and comprises a species selectedfrom the group consisting of the Lewis acid, a precursor to the Lewisacid, the metal carbonyl, and a precursor to the metal carbonyl.

In some embodiments, one of the one or more parameters measured is theconcentration of the Lewis acid, or a decomposition product thereof,within the carbonylation reaction vessel. In some embodiments, theconcentration of the Lewis acid within the carbonylation reaction vesselis measured. In some embodiments, the concentration of a decompositionproduct of the Lewis acid within the carbonylation reaction vessel ismeasured.

In some embodiments, one of the one or more parameters measured is theconcentration of the metal carbonyl, or a decomposition product thereof,within the carbonylation reaction vessel. In some embodiments, theconcentration of the metal carbonyl within the carbonylation reactionvessel is measured. In some embodiments, the concentration of adecomposition product of the metal carbonyl within the carbonylationreaction vessel is measured.

In some embodiments, one of the one or more parameters measured is theconcentration of the Lewis acid, or a decomposition product thereof, inthe product stream downstream from the carbonylation reaction vessel. Insome embodiments, the concentration of the Lewis acid in the productstream downstream from the carbonylation reaction vessel is measured. Insome embodiments, the concentration of a decomposition product of theLewis acid in the product stream downstream from the carbonylationreaction vessel is measured.

In some embodiments, one of the one or more parameters measured is theconcentration of the metal carbonyl, or a decomposition product thereof,in the product stream downstream from the carbonylation reaction vessel.In some embodiments, the concentration of the metal carbonyl in theproduct stream downstream from the carbonylation reaction vessel ismeasured. In some embodiments, the concentration of a decompositionproduct of the metal carbonyl in the product stream downstream from thecarbonylation reaction vessel is measured.

In some embodiments, one of the one or more parameters measured is therate of the carbonylation reaction. In some embodiments, the rate of thecarbonylation reaction is measured by the change in concentration of acarbonylation product in the carbonylation reaction vessel over time. Insome embodiments, the rate of the carbonylation reaction is measured bythe change in concentration of a carbonylation product in the productstream downstream from the carbonylation reaction vessel over time.

In other aspects, provided is a process for continuous carbonylation ofan epoxide or lactone feedstock, comprising:

continuously reacting an epoxide or lactone feedstock with carbonmonoxide in the presence of a carbonylation catalyst in a carbonylationreaction vessel,

-   -   wherein the carbonylation catalyst comprises a Lewis acid and a        metal carbonyl, and    -   wherein at a start time of the process, the carbonylation        reaction vessel contains an initial concentration of the Lewis        acid and an initial concentration of the metal carbonyl; and

adding to the carbonylation reaction vessel, at a time after the starttime of the process, a catalyst replacement component which is differentfrom the catalyst,

-   -   wherein the catalyst replacement component comprises the Lewis        acid, a precursor to the Lewis acid, the metal carbonyl, and a        precursor to the metal carbonyl.

In some embodiments, a rate or time of addition of the catalystreplacement component is based on a rate of depletion of one or both ofthe Lewis acid and the metal carbonyl in the carbonylation reactionvessel. In some variations of the foregoing, one or both of the Lewisacid and the metal carbonyl of the carbonylation catalyst depletes overtime in the carbonylation reaction vessel, and the method furthercomprises determining the depletion.

In certain embodiments of the foregoing, the depletion of one or both ofthe Lewis acid and the metal carbonyl in the carbonylation reactionvessel is determined by:

measuring one or more parameters selected from the group consisting of:

-   -   i-a) a concentration of the Lewis acid in the carbonylation        reaction vessel;    -   i-b) a concentration of a decomposition product of the Lewis        acid in the carbonylation reaction vessel;    -   ii-a) a concentration of the Lewis acid in a process stream        downstream from the carbonylation reaction vessel;    -   ii-b) a concentration of a decomposition product of the Lewis        acid in a process stream downstream from the carbonylation        reaction vessel;    -   iii-a) a concentration of the metal carbonyl in the        carbonylation reaction vessel;    -   iii-b) a concentration of a decomposition product of the metal        carbonyl in the carbonylation reaction vessel;    -   iv-a) a concentration of the metal carbonyl in a process stream        downstream from the carbonylation reaction vessel;    -   iv-b) a concentration of a decomposition product of the metal        carbonyl in a process stream downstream from the carbonylation        reaction vessel; and    -   v) a rate of the carbonylation reaction; and

obtaining a measured value of the one or more parameters.

In some embodiments, the method further comprises:

comparing the measured value of the one or more parameters to apredetermined reference value for each parameter; and

determining a rate of addition or a time of addition of the catalystreplacement component based on the comparison.

In some variations, the rate of addition of the metal carbonyl or aprecursor to the metal carbonyl is increased when the value of ameasurement in parameter iii-b, iv-a, or iv-b, or any combinationthereof, is greater than the predetermined value for each parameter. Insome variations, the rate of addition of the metal carbonyl or aprecursor to the metal carbonyl is increased when the value of ameasurement in parameter iii-a is less than the predetermined value forthe parameter. In other variations, the rate of addition of the Lewisacid or a precursor to the Lewis Acid is increased when the value of ameasurement in parameter i-b, ii-a, or ii-b, or any combination thereof,is greater than the predetermined value for each parameter. In yet othervariations, the rate of addition of the Lewis acid or a precursor to theLewis acid is increased when the value of a measurement in parameter i-ais less than the predetermined value for the parameter.

In some embodiments, the product stream is separated from thecarbonylation reaction vessel by a nanofiltration membrane. In someembodiments, the nanofiltration membrane is selected based on itsability to retain solutes having a molecular weight greater than themolecular weight of the epoxide or lactone carbonylation products, andto allow solutes having lower molecular weights to permeate.

In some embodiments, the catalyst replacement component comprises theLewis acid, or a precursor to the Lewis acid. In some embodiments, thecatalyst replacement component comprises the Lewis acid. In someembodiments, the catalyst replacement component comprises a precursor tothe Lewis acid.

In some embodiments, the catalyst replacement component comprises themetal carbonyl, or a precursor to the metal carbonyl. In someembodiments, the catalyst replacement component comprises the metalcarbonyl. In some embodiments, the catalyst replacement componentcomprises a precursor to the metal carbonyl.

In some embodiments, where more than one catalyst replacement componentis added, each of the one or more catalyst replacement components isadded to the carbonylation reaction vessel separately. In someembodiments, where more than one catalyst replacement component isadded, all of the one or more catalyst replacement components are addedto the carbonylation reaction vessel together.

In some embodiments, each of the one or more catalyst replacementcomponents is added individually to the carbonylation reaction vesselwithout solvent, as a solution in an organic solvent, or as a slurry. Insome embodiments, each of the one or more catalyst replacementcomponents is added to the carbonylation reaction vessel withoutsolvent. In some embodiments, each of the one or more catalystreplacement components is added to the carbonylation reaction vessel asa solution in an organic solvent. In some embodiments, each of the oneor more catalyst replacement components is added to the carbonylationreaction vessel as a slurry.

In certain embodiments, where more than one catalyst replacementcomponent are added, each catalyst replacement component is dissolved insolution, and the solutions are combined enroute to the vessel, e.g., byusing a mixing tee or flowing the combined solutions through a staticmixer.

In certain embodiments, fresh catalyst may also be added to the reactionvessel at the same or different times as the one or more catalystreplacement components.

In certain embodiments, the catalyst replacement components are addedunder an atmosphere comprising CO. In certain embodiments, the CO ispresent at a pressure from about 1 atmosphere to about 400 atmospheres.In certain embodiments, the catalyst replacement components are addedunder an atmosphere comprising CO at a pressure between about 1atmosphere and about 100 atmospheres, or between about 1 atmosphere andabout 50 atmospheres, or between about 10 atmospheres and about 20atmospheres, or between about 5 atmospheres and about 10 atmospheres, orbetween about 1 atmosphere and about 5 atmospheres.

In some embodiments, the amount of a given catalyst replacementcomponent added to the carbonylation reaction vessel is proportional toone of the parameters being measured in step (a). In some embodiments,the amount of a given catalyst replacement component is directlyproportional to changes in the concentration of the parameter measuredin the product stream downstream from the carbonylation reaction vessel.

In some embodiments, if the concentration of the Lewis acid, or adecomposition product thereof, measured in step (a) is increased in theproduct stream downstream from the carbonylation reaction vessel, anamount of Lewis acid that is proportional to the increase in theconcentration of Lewis acid, or a decomposition product thereof,measured in step (a) is added to the carbonylation reaction vessel. Insome embodiments, if the concentration of the Lewis acid, measured instep (a) is found to have decreased within the carbonylation reactionvessel, an amount of Lewis acid, or a precursor to the Lewis acid, thatis proportional to the decrease in the concentration of Lewis acid,measured in step (a) is added to the carbonylation reaction vessel. Forexample, if the concentration of the Lewis acid has decreased by 5%, anamount of the Lewis acid or precursor to the Lewis acid that isequivalent to about 5% of the amount of the Lewis acid initially chargedinto the carbonylation reaction vessel is added. In some embodiments, ifthe concentration of a Lewis acid decomposition product, measured instep (a) is found to have increased within the carbonylation reactionvessel, an amount of Lewis acid, or a precursor to the Lewis acid, thatis proportional to the increase in the concentration of Lewis aciddecomposition product measured in step (a) is added to the carbonylationreaction vessel. For example, if the concentration of the Lewis aciddecomposition product has increased to 5% of the original concentrationof Lewis acid, an amount of the Lewis acid or precursor to the Lewisacid that is equivalent to about 5% of the amount of the Lewis acidinitially charged into the carbonylation reaction vessel is added.

In some embodiments, if the rate of the carbonylation reaction, measuredin step (a) is decreased, an amount of Lewis acid, or a precursor to theLewis acid, that is proportional to the decrease in the rate of thecarbonylation reaction is added to the carbonylation reaction vessel. Insome embodiments, if the rate of the carbonylation reaction, measured instep (a) is decreased, an amount of the metal carbonyl or a precursor tothe metal carbonyl, that is proportional to the decrease in the rate ofthe carbonylation reaction is added to the carbonylation reactionvessel. For example, if the rate of the carbonylation reaction hasdecreased by 5%, an amount of Lewis acid, precursor to the Lewis acid,metal carbonyl, or precursor to the metal carbonyl that is equivalent toabout 5% of the amount of the Lewis acid or metal carbonyl initiallycharged into the carbonylation reaction vessel is added.

In some embodiments, if the concentration of the metal carbonyl,measured in step (a) is increased in the product stream downstream fromthe carbonylation reaction vessel, an amount of metal carbonyl, or aprecursor to the metal carbonyl that is proportional to the increase inthe amount of metal carbonyl measured in step (a) is added to thecarbonylation reaction vessel. In some embodiments, if the concentrationof the metal carbonyl measured in step (a) is decreased within thecarbonylation reaction vessel, an amount of metal carbonyl, or aprecursor to the metal carbonyl, that is proportional to the decrease inthe amount of metal carbonyl measured in step (a) is added to thecarbonylation reaction vessel. For example, if the concentration of themetal carbonyl has decreased by 5%, an amount of the metal carbonyl orprecursor to the metal carbonyl that is equivalent to about 5% of theamount of the metal carbonyl initially charged into the carbonylationreaction vessel is added. In some embodiments, if the concentration ofthe metal carbonyl decomposition product measured in step (a) isincreased within the carbonylation reaction vessel, an amount of metalcarbonyl, or a precursor to the metal carbonyl, that is proportional tothe increase in the amount of metal carbonyl decomposition productmeasured in step (a) is added to the carbonylation reaction vessel. Forexample, if the concentration of the metal carbonyl decompositionproduct has increased to 5% of the initial concentration of metalcarbonyl initially charged into the carbonylation reaction vessel, thenan amount of the metal carbonyl or precursor to the metal carbonyl thatis equivalent to about 5% of the amount of the metal carbonyl initiallycharged is added.

II. Carbonylation Catalyst

As described generally above, carbonylation catalysts utilized in theprocesses described herein comprise a Lewis acid and a metal carbonyl.Typically, in one variation, a single metal carbonyl compound isprovided, but in some embodiments, mixtures of two or more metalcarbonyl compounds are provided. Thus, when a provided metal carbonylcompound “comprises”, e.g., a neutral metal carbonyl compound, it isunderstood that the provided metal carbonyl compound can be a singleneutral metal carbonyl compound, or a neutral metal carbonyl compound incombination with one or more metal carbonyl compounds. Preferably, theprovided metal carbonyl compound is capable of ring-opening an epoxideand facilitating the insertion of CO into the resulting metal carbonbond. Metal carbonyl compounds with this reactivity are well known inthe art and are used for laboratory experimentation as well as inindustrial processes such as hydroformylation.

In some embodiments, the metal carbonyl compound comprises an anionicmetal carbonyl moiety. In other embodiments, the metal carbonyl compoundcomprises a neutral metal carbonyl compound. In some embodiments, themetal carbonyl compound comprises a metal carbonyl hydride or a hydridometal carbonyl compound. In some embodiments, the metal carbonylcompound acts as a pre-catalyst which reacts in situ with one or morereaction components to provide an active species different from thecompound initially provided. Such pre-catalysts are specificallyencompassed as it is recognized that the active species in a givenreaction may not be known with certainty; thus the identification ofsuch a reactive species in situ does not itself depart from the spiritor teachings herein.

In certain embodiments, the hydrido metal carbonyl (either as providedor generated in situ) comprises one or more of HCo(CO)₄, HCoQ(CO)₃,HMn(CO)₅, HMn(CO)₄Q, HW(CO)₃Q, HRe(CO)₅, HMo(CO)₃Q, HOs(CO)₂Q,HMo(CO)₂Q₂, HFe(CO₂)Q, HW(CO)₂Q₂, HRuCOQ₂, H₂Fe(CO)₄ or H₂Ru(CO)₄, whereeach Q is independently as defined above and in the classes andsubclasses herein. In certain embodiments, the metal carbonyl hydride(either as provided or generated in situ) comprises HCo(CO)₄. In certainembodiments, the metal carbonyl hydride (either as provided or generatedin situ) comprises HCo(CO)₃PR₃, where each R is independently anoptionally substituted aryl group, an optionally substituted C₁₋₂₀aliphatic group, an optionally substituted C₁₋₁₀ alkoxy group, or anoptionally substituted phenoxy group. In certain embodiments, the metalcarbonyl hydride (either as provided or generated in situ) comprisesHCo(CO)₃cp, where cp represents an optionally substituted pentadienylligand. In certain embodiments, the metal carbonyl hydride (either asprovided or generated in situ) comprises HMn(CO)₅. In certainembodiments, the metal carbonyl hydride (either as provided or generatedin situ) comprises H₂Fe(CO)₄.

In some embodiments, the metal carbonyl compound comprises an anionicmetal carbonyl species. In some embodiments, such anionic metal carbonylspecies have the general formula [Q_(d)M′_(e)(CO)_(w)]^(y−), where Q isany ligand and need not be present, M′ is a metal atom, d is an integerbetween 0 and 8 inclusive, e is an integer between 1 and 6 inclusive, wis a number such as to provide the stable anionic metal carbonylcomplex, and y is the charge of the anionic metal carbonyl species. Insome embodiments, the anionic metal carbonyl has the general formula[QM′(CO)_(w)]^(y−), where Q is any ligand and need not be present, M′ isa metal atom, w is a number such as to provide the stable anionic metalcarbonyl, and y is the charge of the anionic metal carbonyl.

In some embodiments, the anionic metal carbonyl species includemonoanionic carbonyl complexes of metals from groups 5, 7 or 9 of theperiodic table or dianionic carbonyl complexes of metals from groups 4or 8 of the periodic table. In some embodiments, the anionic metalcarbonyl compound contains cobalt or manganese. In some embodiments, theanionic metal carbonyl compound contains rhodium. Suitable anionic metalcarbonyl compounds include, for example, [Co(CO)₄]⁻, [Ti(CO)₆]²⁻,[V(CO)₆]⁻, [Rh(CO)₄]⁻, [Fe(CO)₄]²⁻, [Ru(CO)₄]²⁻, [Os(CO)₄]²⁻,[Cr₂(CO)₁₀]²⁻, [Fe₂(CO)₈]²⁻, [Tc(CO)₅]⁻, [Re(CO)₅]⁻, and [Mn(CO)₅]⁻. Insome embodiments, the anionic metal carbonyl comprises [Co(CO)₄]⁻. Insome embodiments, a mixture of two or more anionic metal carbonylcomplexes may be present in the carbonylation catalysts used in themethods.

The term “such as to provide a stable anionic metal carbonyl” for[Q_(d)M′_(e)(CO)_(w)]^(y−) is used herein to mean that[Q_(d)M′_(e)(CO)_(w)]^(y−) is a species characterizable by analyticalmeans, e.g., NMR, IR, X-ray crystallography, Raman spectroscopy and/orelectron spin resonance (EPR) and isolable in catalyst form in thepresence of a suitable cation or a species formed in situ. It is to beunderstood that metals which can form stable metal carbonyl complexeshave known coordinative capacities and propensities to form polynuclearcomplexes which, together with the number and character of optionalligands Q that may be present and the charge on the complex willdetermine the number of sites available for CO to coordinate andtherefore the value of w. Typically, such compounds conform to the“18-electron rule”. Such knowledge is within the grasp of one havingordinary skill in the arts pertaining to the synthesis andcharacterization of metal carbonyl compounds.

In embodiments where the metal carbonyl compound is an anionic species,one or more cations must also necessarily be present. The presentdisclosure places no particular constraints on the identity of suchcations. For example, in certain embodiments, the metal carbonyl anionis associated with a cationic Lewis acid. In other embodiments a cationassociated with a provided anionic metal carbonyl compound is a simplemetal cation such as those from Groups 1 or 2 of the periodic table(e.g. Na⁺, Li⁺, K⁺, and Mg²⁺). In other embodiments a cation associatedwith a provided anionic metal carbonyl compound is a bulky nonelectrophilic cation such as an ‘onium salt’ (e.g. Bu₄N⁺, PPM⁺, Ph₄P⁺,and Ph₄As⁺). In other embodiments, a metal carbonyl anion is associatedwith a protonated nitrogen compound (e.g., a cation may comprise acompound such as MeTBD-H⁺, DMAP-H⁺, DABCO-H⁺, and DBU-H⁺). In someembodiments, compounds comprising such protonated nitrogen compounds areprovided as the reaction product between an acidic hydrido metalcarbonyl compound and a basic nitrogen-containing compound (e.g., amixture of DBU and HCo(CO)₄).

In certain embodiments, the metal carbonyl compound comprises a neutralmetal carbonyl. In certain embodiments, such neutral metal carbonylcompounds have the general formula Q_(d)M′e(CO)_(w′), where Q is anyligand and need not be present, M′ is a metal atom, d is an integerbetween 0 and 8 inclusive, e is an integer between 1 and 6 inclusive,and w′ is a number such as to provide the stable neutral metal carbonylcomplex. In certain embodiments, the neutral metal carbonyl has thegeneral formula QM′(CO)_(w′). In certain embodiments, the neutral metalcarbonyl has the general formula M′(CO)_(w′). In certain embodiments,the neutral metal carbonyl has the general formula QM′₂(CO)_(w′). Incertain embodiments, the neutral metal carbonyl has the general formulaM′₂(CO)_(w′). Suitable neutral metal carbonyl compounds include, forexample, Ti(CO)₇, V₂(CO)₁₂, Cr(CO)₆, Mo(CO)₆, W(CO)₆, Mn₂(CO)₁₀,Tc₂(CO)₁₀, Re₂(CO)₁₀, Fe(CO)₅, Ru(CO)₅, Os(CO)₅, Ru₃(CO)₁₂,Os₃(CO)₁₂Fe₃(CO)₁₂, Fe₂(CO)₉, Co₄(CO)₁₂, Rh₄(CO)₁₂, Rh₆(CO)₁₆,Ir₄(CO)₁₂, Co₂(CO)₈, and Ni(CO)₄.

The term “such as to provide a stable neutral metal carbonyl forQ_(d)M′_(e)(CO)_(w′)” is used herein to mean that Q_(d)M′_(e)(CO)_(w′),is a species that may be characterized by analytical means, e.g., NMR,IR, X-ray crystallography, Raman spectroscopy and/or electron spinresonance (EPR) and isolable in pure form or a species formed in situ.It is to be understood that metals which can form stable metal carbonylcomplexes have known coordinative capacities and propensities to formpolynuclear complexes which, together with the number and character ofoptional ligands Q that may be present will determine the number ofsites available for CO to coordinate and therefore the value of w′.Typically, such compounds conform to stoichiometries conforming to the“18-electron rule”. Such knowledge is within the grasp of one havingordinary skill in the arts pertaining to the synthesis andcharacterization of metal carbonyl compounds.

In some embodiments, no ligands Q are present on the metal carbonylcompound. In other embodiments, one or more ligands Q are present on themetal carbonyl compound. In some embodiments, where Q is present, eachoccurrence of Q is selected from the group consisting of phosphineligands, amine ligands, cyclopentadienyl ligands, heterocyclic ligands,nitriles, phenols, and combinations of two or more of these. In someembodiments, one or more of the CO ligands of any of the metal carbonylcompounds described above is replaced with a ligand Q. In someembodiments, Q is a phosphine ligand. In some embodiments, Q is atriaryl phosphine. In some embodiments, Q is trialkyl phosphine. In someembodiments, Q is a phosphite ligand. In some embodiments, Q is anoptionally substituted cyclopentadienyl ligand. In some embodiments, Qis cp. In some embodiments, Q is cp*. In some embodiments, Q is an amineor a heterocycle.

In certain embodiments, for any of the metal carbonyl compoundsdescribed above, M′ comprises a transition metal. In certainembodiments, for any of the metal carbonyl compounds described above, M′is selected from Groups 5 (Ti) to 10 (Ni) of the periodic table. Incertain embodiments, M′ is a Group 9 metal. In certain embodiments, M′is Co. In certain embodiments, M′ is Rh. In certain embodiments, M′ isIr. In certain embodiments, M′ is Fe. In certain embodiments, M′ is Mn.

As described generally above, carbonylation catalysts utilized in theprocesses described herein comprise a Lewis acid. In some embodiments,the carbonylation catalyst includes an anionic metal carbonyl complexand a cationic Lewis acidic component. In some embodiments, the metalcarbonyl complex includes a carbonyl cobaltate and the Lewis acidicco-catalyst includes a metal-centered cationic Lewis acid. In someembodiments, an included Lewis acid comprises a boron compound.

In some embodiments, where an included Lewis acid comprises a boroncompound, the boron compound comprises a trialkyl boron compound or atriaryl boron compound. In some embodiments, an included boron compoundcomprises one or more boron-halogen bonds. In some embodiments, where anincluded boron compound comprises one or more boron-halogen bonds, thecompound is a dialkyl halo boron compound (e.g., R₂BX), a dihalomonoalkyl compound (e.g., RBX₂), an aryl halo boron compound (e.g.,Ar₂BX or ArBX₂), or a trihalo boron compound (e.g., BCl₃ or BBr₃),wherein each R is an alkyl group; each X is a halogen; and each Ar is anaromatic group.

In some embodiments, where the included Lewis acid comprises ametal-centered cationic Lewis acid, the Lewis acid is a cationic metalcomplex. In some embodiments, the cationic metal complex has its chargebalanced either in part, or wholly by one or more anionic metal carbonylmoieties. Suitable anionic metal carbonyl compounds include thosedescribed above. In some embodiments, there are 1 to 17 such anionicmetal carbonyls balancing the charge of the cationic metal complex. Insome embodiments, there are 1 to 9 such anionic metal carbonylsbalancing the charge of the metal complex. In some embodiments, thereare 1 to 5 such anionic metal carbonyls balancing the charge of themetal complex. In some embodiments, there are 1 to 3 such anionic metalcarbonyls balancing the charge of the metal complex.

In some embodiments, where carbonylation catalysts used in methodsdescribed herein include a cationic metal complex, the metal complex hasthe formula [(L^(c))_(v)M_(b)]^(z+), where:

L^(c) is a ligand where, when two or more L^(c) are present, each may bethe same or different;

M is a metal atom where, when two M are present, each may be the same ordifferent;

v is an integer from 1 to 4 inclusive;

b is an integer from 1 to 2 inclusive; and

z is an integer greater than 0 that represents the cationic charge onthe metal complex.

In some embodiments, provided Lewis acids conform to structure I:

wherein:

is a multidentate ligand;

M is a metal atom coordinated to the multidentate ligand;

a is the charge of the metal atom and ranges from 0 to 2; and

In some embodiments, provided metal complexes conform to structure II:

where a is as defined above (each a may be the same or different), and

M¹ is a first metal atom;

M² is a second metal atom; and

comprises a multidentate ligand system capable of coordinating bothmetal atoms.

For sake of clarity, and to avoid confusion between the net and totalcharge of the metal atoms in complexes I and II and other structuresherein, the charge (a⁺) shown on the metal atom in complexes I and IIabove represents the net charge on the metal atom after it has satisfiedany anionic sites of the multidentate ligand. For example, if a metalatom in a complex of formula I were Cr(III), and the ligand wereporphyrin (a tetradentate ligand with a charge of −2), then the chromiumatom would have a net charge of +1, and a would be 1.

Suitable multidentate ligands include, for example, porphyrin ligands 1,salen ligands 2, dibenzotetramethyltetraaza[14]annulene (tmtaa) ligands3, phthalocyaninate ligands 4, the Trost ligand 5, tetraphenylporphyrinligands 6, and corrole ligands 7. In some embodiments, the multidentateligand is a salen ligand. In other embodiments, the multidentate ligandis a porphyrin ligand. In other embodiments, the multidentate ligand isa tetraphenylporphyrin ligand. In other embodiments, the multidentateligand is a corrole ligand. Any of the foregoing ligands can beunsubstituted or can be substituted. Numerous variously substitutedanalogs of these ligands are known in the art and will be apparent tothe skilled artisan.

where each of R^(c), R^(d), R^(1a), R^(2a), R^(3a), R^(4a), R^(1a′),R^(2a′), R^(3a′), and M, is as defined and described in the classes andsubclasses herein.

In some embodiments, Lewis acids provided carbonylation catalysts usedin methods described herein comprise metal-porphinato complexes. In someembodiments, the moiety

has the structure:

-   -   where each of M and a is as defined above and described in the        classes and subclasses herein, and    -   R^(d) at each occurrence is independently hydrogen, halogen,        —OR⁴, —NR^(y) ₂, —SR^(y), —CN, —NO₂, —SO₂R^(y), —SOR^(y),        —SO₂NR^(y) ₂; —CNO, —NR^(y)SO₂R^(y), —NCO, —N₃, —SiR^(y) ₃; or        an optionally substituted group selected from the group        consisting of C₁₋₂₀ aliphatic; C₁₋₂₀ heteroaliphatic having 1-4        heteroatoms independently selected from the group consisting of        nitrogen, oxygen, and sulfur; 6- to 10-membered aryl; 5- to        10-membered heteroaryl having 1-4 heteroatoms independently        selected from nitrogen, oxygen, and sulfur; and 4- to 7-membered        heterocyclic having 1-2 heteroatoms independently selected from        the group consisting of nitrogen, oxygen, and sulfur, where two        or more R^(d) groups may be taken together to form one or more        optionally substituted rings;    -   each R^(y) is independently hydrogen, an optionally substituted        group selected the group consisting of acyl; carbamoyl,        arylalkyl; 6- to 10-membered aryl; C₁₋₁₂ aliphatic; C₁₋₁₂        heteroaliphatic having 1-2 heteroatoms independently selected        from the group consisting of nitrogen, oxygen, and sulfur; 5- to        10-membered heteroaryl having 1-4 heteroatoms independently        selected from the group consisting of nitrogen, oxygen, and        sulfur; 4- to 7-membered heterocyclic having 1-2 heteroatoms        independently selected from the group consisting of nitrogen,        oxygen, and sulfur; an oxygen protecting group; and a nitrogen        protecting group; two R^(y) on the same nitrogen atom are taken        with the nitrogen atom to form an optionally substituted 4- to        7-membered heterocyclic ring having 0-2 additional heteroatoms        independently selected from the group consisting of nitrogen,        oxygen, and sulfur; and    -   each R⁴ is independently is a hydroxyl protecting group or        R^(y).

In some embodiments, the moiety

has the structure:

where M, a and R^(d) are as defined above and in the classes andsubclasses herein.

In some embodiments, the moiety

has the structure:

where M, a and R^(d) are as defined above and in the classes andsubclasses herein.

In some embodiments, Lewis acids included in carbonylation catalystsused in methods described herein comprise metallo salenate complexes. Insome embodiments, the moiety

has the structure:

wherein:

-   -   M, and a are as defined above and in the classes and subclasses        herein.    -   R^(1a), R^(1a′), R^(2a), R^(2a′), R^(3a), and R^(3a′) are        independently hydrogen, halogen, —OR⁴, —NR^(y) ₂, —CN, —NO₂,        —SO₂R^(y), —SOR^(y), —SO₂NR^(y) ₂; —CNO, —NR^(y)SO₂R^(y), —NCO,        —N₃, —SiR^(y) ₃; or an optionally substituted group selected        from the group consisting of C₁₋₂₀ aliphatic; C₁₋₂₀        heteroaliphatic having 1-4 heteroatoms independently selected        from the group consisting of nitrogen, oxygen, and sulfur; 6- to        10-membered aryl; 5- to 10-membered heteroaryl having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur; and 4- to 7-membered heterocyclic having 1-2 heteroatoms        independently selected from the group consisting of nitrogen,        oxygen, and sulfur; wherein each R⁴, and R^(y) is independently        as defined above and described in classes and subclasses herein,    -   wherein any of (R^(2a′) and R^(3a′)), (R^(2a) and R^(3a)),        (R^(1a) and R^(2a)), and (R^(1a′) and R^(2a′)) may optionally be        taken together with the carbon atoms to which they are attached        to form one or more rings which may in turn be substituted with        one or more R^(y) groups; and    -   R^(4a) is selected from the group consisting of:

where

-   -   R^(c) at each occurrence is independently hydrogen, halogen,        —OR⁴, —NR^(y) ₂, —SR^(y), —CN, —NO₂, —SO₂R^(y), —SOR^(y),        —SO₂NR^(y) ₂; —CNO, —NR^(y)SO₂R^(y), —NCO, —N₃, —SiR^(y) ₃; or        an optionally substituted group selected from the group        consisting of C₁₋₂₀ aliphatic; C₁₋₂₀ heteroaliphatic having 1-4        heteroatoms independently selected from the group consisting of        nitrogen, oxygen, and sulfur; 6- to 10-membered aryl; 5- to        10-membered heteroaryl having 1-4 heteroatoms independently        selected from nitrogen, oxygen, and sulfur; and 4- to 7-membered        heterocyclic having 1-2 heteroatoms independently selected from        the group consisting of nitrogen, oxygen, and sulfur;    -   where:        -   two or more R^(c) groups may be taken together with the            carbon atoms to which they are attached and any intervening            atoms to form one or more rings;        -   when two R^(c) groups are attached to the same carbon atom,            they may be taken together along with the carbon atom to            which they are attached to form a moiety selected from the            group consisting of: a 3- to 8-membered spirocyclic ring, a            carbonyl, an oxime, a hydrazone, an imine; and an optionally            substituted alkene;    -   where R⁴ and R^(y) are as defined above and in classes and        subclasses herein;    -   Y is a divalent linker selected from the group consisting of:        —NR^(y)—, —N(R^(y))C(O)—, —C(O)NR^(y)—, —O—, —C(O)—, —OC(O)—,        —C(O)O—, —S—, —SO—, —SO₂—, —C(═S)—, —C(═NR^(y))—, —N═N—; a        polyether; a C₃ to C₈ substituted or unsubstituted carbocycle;        and a C₁ to C₈ substituted or unsubstituted heterocycle;    -   m′ is 0 or an integer from 1 to 4, inclusive;    -   q is 0 or an integer from 1 to 4, inclusive; and    -   x is 0, 1, or 2.

In some embodiments, a provided Lewis acid comprises a metallo salencompound, as shown in formula Ia:

-   -   wherein each of M, R^(d), and a, is as defined above and in the        classes and subclasses herein,

represents is an optionally substituted moiety linking the two nitrogenatoms of the diamine portion of the salen ligand, where

is selected from the group consisting of a C₃-C₁₄ carbocycle, a C₆-C₁₀aryl group, a C₃-C₁₄ heterocycle, and a C₅-C₁₀ heteroaryl group; or anoptionally substituted C₂₋₂₀ aliphatic group, wherein one or moremethylene units are optionally and independently replaced by —NR^(y)—,—N(R^(y))C(O)—, —C(O)N(R^(y))—, —OC(O)N(R^(y))—, —N(R^(y))C(O)O—,—OC(O)O—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO₂—, —C(═S)—,—C(═NR^(y))—, —C(═NOR^(y))— or —N═N—.

In some embodiments metal complexes having formula Ia above, at leastone of the phenyl rings comprising the salicylaldehyde-derived portionof the metal complex is independently selected from the group consistingof:

In some embodiments, a provided Lewis acid comprises a metallo salencompound, conforming to one of formulae Va or Vb:

-   -   where M, a, R^(d), R^(1a), R^(3a), R^(1a′), R^(3a′), and

are as defined above and in the classes and subclasses herein.

In some embodiments of metal complexes having formulae Va or Vb, eachR^(1a) and R^(3a) is, independently, optionally substituted C₁-C₂₀aliphatic.

In some embodiments, the moiety

comprises an optionally substituted 1,2-phenyl moiety.

In some embodiments, Lewis acids included in carbonylation catalystsused in methods described herein comprise metal-tmtaa complexes. In someembodiments, the moiety

has the structure:

-   where M, a and R^(d) are as defined above and in the classes and    subclasses herein, and-   R^(e) at each occurrence is independently hydrogen, halogen, —OR,    —NR^(y) ₂, —SR^(y), —CN, —NO₂, —SO₂R^(y), —SOR^(y), —SO₂NR^(y) ₂;    —CNO, —NR^(y)SO₂R^(y), —NCO, —N₃, —SiR^(y) ₃; or an optionally    substituted group selected from the group consisting of C₁₋₂₀    aliphatic; C₁₋₂₀ heteroaliphatic having 1-4 heteroatoms    independently selected from the group consisting of nitrogen,    oxygen, and sulfur; 6- to 10-membered aryl; 5- to 10-membered    heteroaryl having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur; and 4- to 7-membered heterocyclic    having 1-2 heteroatoms independently selected from the group    consisting of nitrogen, oxygen, and sulfur.

In some embodiments, the moiety

has the structure:

-   -   where each of M, a, R^(c) and R^(d) is as defined above and in        the classes and subclasses herein.

In some embodiments, where carbonylation catalysts used in methodsdescribed herein include a Lewis acidic metal complex, the metal atom isselected from the periodic table groups 2-13, inclusive. In someembodiments, M is a transition metal selected from the periodic tablegroups 4, 6, 11, 12 and 13. In some embodiments, M is aluminum,chromium, titanium, indium, gallium, zinc cobalt, or copper. In someembodiments, M is aluminum. In other embodiments, M is chromium.

In some embodiments, M has an oxidation state of +2. In someembodiments, M is Zn(II), Cu(II), Mn(II), Co(II), Ru(II), Fe(II),Co(II), Rh(II), Ni(II), Pd(II) or Mg(II). In some embodiments M isZn(II). In some embodiments M is Cu(II).

In some embodiments, M has an oxidation state of +3. In someembodiments, M is Al(III), Cr(III), Fe(III), Co(III), Ti(III) In(III),Ga(III) or Mn(III). In some embodiments M is Al(III). In someembodiments M is Cr(III).

In some embodiments, M has an oxidation state of +4. In someembodiments, M is Ti(IV) or Cr(IV).

In some embodiments, M¹ and M² are each independently a metal atomselected from the periodic table groups 2-13, inclusive. In someembodiments, M is a transition metal selected from the periodic tablegroups 4, 6, 11, 12 and 13. In some embodiments, M is aluminum,chromium, titanium, indium, gallium, zinc cobalt, or copper. In someembodiments, M is aluminum. In other embodiments, M is chromium. In someembodiments, M¹ and M² are the same. In some embodiments, M¹ and M² arethe same metal, but have different oxidation states. In someembodiments, M¹ and M² are different metals.

In some embodiments, one or more of M¹ and M² has an oxidation state of+2. In some embodiments, M¹ is Zn(II), Cu(II), Mn(II), Co(II), Ru(II),Fe(II), Co(II), Rh(II), Ni(II), Pd(II) or Mg(II). In some embodiments M¹is Zn(II). In some embodiments M¹ is Cu(II). In some embodiments, M² isZn(II), Cu(II), Mn(II), Co(II), Ru(II), Fe(II), Co(II), Rh(II), Ni(II),Pd(II) or Mg(II). In some embodiments M² is Zn(II). In some embodimentsM² is Cu(II).

In some embodiments, one or more of M¹ and M² has an oxidation state of+3. In some embodiments, M¹ is Al(III), Cr(III), Fe(III), Co(III),Ti(III) In(III), Ga(III) or Mn(III). In some embodiments M¹ is Al(III).In some embodiments M¹ is Cr(III). In some embodiments, M² is Al(III),Cr(III), Fe(III), Co(III), Ti(III) In(III), Ga(III) or Mn(III). In someembodiments M² is Al(III). In some embodiments M² is Cr(III).

In some embodiments, one or more of M¹ and M² has an oxidation state of+4. In some embodiments, M¹ is Ti(IV) or Cr(IV). In some embodiments, M²is Ti(IV) or Cr(IV).

In some embodiments, the metal-centered Lewis-acidic component of thecarbonylation catalyst includes a dianionic tetradentate ligand. In someembodiments, the dianionic tetradentate ligand is selected from thegroup consisting of: porphyrin ligands; salen ligands;dibenzotetramethyltetraaza[14]annulene (tmtaa) ligands; phthalocyaninateligands; and the Trost ligand.

In some embodiments, the carbonylation catalyst includes a carbonylcobaltate in combination with an aluminum porphyrin compound. In someembodiments, the carbonylation catalyst is [(TPP)Al(THF)₂][Co(CO)₄]where TPP stands for tetraphenylporphyrin and THF stands fortetrahydrofuran.

In some embodiments, the carbonylation catalyst includes a carbonylcobaltate in combination with a chromium porphyrin compound.

In some embodiments, the carbonylation catalyst includes a carbonylcobaltate in combination with a chromium salen compound. In someembodiments, the carbonylation catalyst includes a carbonyl cobaltate incombination with a chromium salophen compound.

In some embodiments, the carbonylation catalyst includes a carbonylcobaltate in combination with an aluminum salen compound. In someembodiments, the carbonylation catalyst includes a carbonyl cobaltate incombination with an aluminum salophen compound.

In some embodiments, one or more neutral two electron donors coordinateto M, M¹ or M² and fill the coordination valence of the metal atom. Insome embodiments, the neutral two electron donor is a solvent molecule.In some embodiments, the neutral two electron donor is an ether. In someembodiments, the neutral two electron donor is tetrahydrofuran, diethylether, acetonitrile, carbon disulfide, or pyridine. In some embodiments,the neutral two electron donor is tetrahydrofuran. In some embodiments,the neutral two electron donor is an epoxide. In some embodiments, theneutral two electron donor is an ester or a lactone.

III. Catalyst Replacement Components

As described generally above, each of the one or more catalystreplacement components described herein comprise species independentlyselected from the group consisting of the Lewis acid, a precursor to theLewis acid, the metal carbonyl, or a precursor to the metal carbonyl. Insome embodiments one of the one or more catalyst replacement componentscomprises the Lewis acid. In some embodiments one of the one or morecatalyst replacement components comprises a precursor to the Lewis acid.In some embodiments one of the one or more catalyst replacementcomponents comprises the metal carbonyl. In some embodiments one of theone or more catalyst replacement components comprises a precursor to themetal carbonyl.

In certain embodiments, the Lewis acid used as a catalyst replacementcomponent is selected from the Lewis acids described in classes andsubclasses above in Section II describing the catalysts. One of skill inthe art will appreciate that where a given Lewis acid is ionized, it isaccompanied by a counterion. Where the catalyst is an ionic pair of acharged Lewis acid and a charged metal carbonyl, if only the Lewis acidis to be added as a catalyst replacement component, then it must beadded together with a counterion to be substituted by the charged metalcarbonyl once inside the carbonylation reaction vessel.

The addition of the Lewis acid (either as a neutral or ionic species) isdistinguished from the addition of a Lewis acid precursor. The term“Lewis acid precursor”, as used herein is defined as a species, otherthan a Lewis acid or salt thereof, that when added to the carbonylationreaction vessel, regenerates the Lewis acid species when contacted byone or more other components within the carbonylation reaction vessel.Lewis acid precursors may include, for example, multidentate ligands andmultidentate ligand systems (with or without coordinated metal atoms),neutral two-electron donors, and labile metal sources such as metalsincluding a carbon-metal bond. Suitable multidentate ligands and neutraltwo-electron donors are described in Section II describing thecatalysts, and described herein in classes and subclasses. Suitablelabile metal sources include, for example, alkyl metals (e.g.,trialkylaluminums, and trialkylchromiums), or aryl metals (e.g.,triarylaluminums, and triarylchromiums).

In some embodiments, a Lewis acid precursor includes a multidentateligand of one of the following formulas:

where each of R^(c), R^(d), R^(1a), R^(2a), R^(3a), R^(4a), R^(1a′),R^(2a′), and R^(3a′), is as defined and described in the classes andsubclasses herein.

In some embodiments, Lewis acid precursors have the following formula:

wherein:

is a multidentate ligand;

M is a metal atom coordinated to the multidentate ligand; and

R^(q) is selected from C₁₋₁₂ aliphatic and optionally substituted aryl.

In some embodiments, Lewis acid precursors have the following formula:

wherein:

M¹ is a first metal atom;

M² is a second metal atom;

comprises a multidentate ligand system capable of coordinating bothmetal atoms; and

each R^(q) is independently selected from C₁₋₁₂ aliphatic and optionallysubstituted aryl.

In some embodiments, R^(q) is C₁₋₆ aliphatic. In some embodiments, R^(q)is methyl. In some embodiments, R^(q) is ethyl. In some embodiments,R^(q) is optionally substituted aryl. In some embodiments, R^(q) isoptionally substituted phenyl. In some embodiments, R^(q) is phenyl.

In certain embodiments, the metal carbonyl used as a catalystreplacement component is selected from the metal carbonyls described inclasses and subclasses above in Section II (“Catalysts”). One of skillin the art will appreciate that where a given metal carbonyl is ionized,it is accompanied by a counterion. Where the catalyst is an ionic pairof a charged Lewis acid and a charged metal carbonyl, if only the metalcarbonyl is to be added as a catalyst replacement component, then itmust be added together with a counterion which will subsequently besubstituted by the charged Lewis acid in situ.

The addition of the metal carbonyl (either as a neutral or ionicspecies) is distinguished from the addition of a metal carbonylprecursor. The term “metal carbonyl precursor”, as used herein isdefined as a species that, when added to the carbonylation reactionvessel, regenerates the metal carbonyl species when contacted by one ormore other components within the carbonylation reaction vessel. Examplesof metal carbonyl precursors include, for example, neutral metalcarbonyl compounds.

In some embodiments, such neutral metal carbonyl compounds have thegeneral formula Q_(d)M′_(e)(CO)_(w′), where Q is any ligand and need notbe present, M′ is a metal atom, d is an integer between 0 and 8inclusive, e is an integer between 1 and 6 inclusive, and w′ is a numbersuch as to provide the stable neutral metal carbonyl complex. In someembodiments, the neutral metal carbonyl has the general formulaQM′(CO)_(w′). In some embodiments, the neutral metal carbonyl has thegeneral formula M′₂(CO)_(w′). In some embodiments, the neutral metalcarbonyl has the general formula QM′₂(CO)_(w′). In some embodiments, theneutral metal carbonyl has the general formula M′₂(CO)_(w′). Suitableneutral metal carbonyl compounds include, for example, Ti(CO)₇;V₂(CO)₁₂; Cr(CO)₆; Mo(CO)₆; W(CO)₆; Mn₂(CO)₁₀; Tc₂(CO)₁₀; Re₂(CO)₁₀;Fe(CO)₅; Ru(CO)₅; Os(CO)₅; Ru₃(CO)₁₂; Os₃(CO)₁₂; Fe₃(CO)₁₂; Fe₂(CO)₉;Co₄(CO)₁₂; Rh₄(CO)₁₂; Rh₆(CO)₁₆; Ir₄(CO)₁₂; Co₂(CO)₈; and Ni(CO)₄. Insome embodiments, the metal carbonyl precursor is Co₄(CO)₁₂ or Co₂(CO)₈.In some embodiments, the metal carbonyl precursor is Co₂(CO)₈. In someembodiments, the metal carbonyl precursor is Co₄(CO)₁₂. In certainembodiments, the metal carbonyl precursor is a mixture of two or morecobalt carbonyl species.

In some embodiments, if the Lewis acid or metal carbonyl used ascatalyst replacement components are added in ionic form, theircounterions are selected to minimize contamination with halide and/oralkali metal ions. In certain embodiments, the catalyst replacementcomponents are essentially free of halide. In certain embodiments, thecatalyst replacement components have a halide content less than about200 ppm. In certain embodiments, the catalyst replacement componentshave a halide content less than about 150 ppm, less than about 100 ppm,less than about 50 ppm, less than about 40 ppm, less than about 30 ppm,less than about 20 ppm, less than about 10 ppm, less than about 5 ppm,less than about 2 ppm, or less than about 1 ppm. In certain embodiments,the catalyst replacement components are essentially free of alkali metalions. In certain embodiments, the catalyst replacement components havean alkali metal ion content less than about 200 ppm. In certainembodiments, the catalyst replacement components have an alkali metalion content less than about 150 ppm, less than about 100 ppm, less thanabout 50 ppm, less than about 40 ppm, less than about 30 ppm, less thanabout 20 ppm, less than about 10 ppm, less than about 5 ppm, less thanabout 2 ppm, or less than about 1 ppm.

In some embodiments, a given catalyst replacement component is recycledfrom the product stream.

IV. Processes for Replacement of Catalyst Component at PredeterminedRate

In another aspect, provided is a process for continuous carbonylation ofan epoxide or lactone feedstock, the process comprising:

reacting an epoxide or lactone feedstock with carbon monoxide in thepresence of a catalyst comprising a Lewis acid and a metal carbonyl in acarbonylation reaction vessel; and

continuously or intermittently introducing to the carbonylation reactionvessel a catalyst replacement component which is different from thecatalyst and comprises a species selected from the group consisting ofthe Lewis acid, a precursor to the Lewis acid, the metal carbonyl, and aprecursor to the metal carbonyl.

In some embodiments, the catalyst replacement component comprises theLewis acid. In some embodiments, the catalyst replacement componentcomprises a precursor to the Lewis acid. In some embodiments, thecatalyst replacement component comprises the metal carbonyl. In someembodiments, the catalyst replacement component comprises a precursor tothe metal carbonyl.

Suitable catalyst replacement components (e.g., Lewis acids, precursorsto Lewis acids, metal carbonyls, and precursors to metal carbonyls) aredescribed in Section III above.

In some embodiments, the catalyst replacement component is introduced ata rate that results in less than 10% variation in the rate of thecarbonylation reaction over a period of one hour. In some embodiments,the catalyst replacement component is introduced at a rate that resultsin less than 5% variation in the rate of the carbonylation reaction overa period of one hour.

In some embodiments, the rate at which the catalyst replacementcomponent is added to the carbonylation reaction vessel is determined bythe rate at which the carbonylation reaction rate has been observed todecrease. In some embodiments, the rate at which the one or morecatalyst replacement components are added to the carbonylation reactionvessel is directly proportional to the rate at which the carbonylationreaction rate has been observed to decrease.

In some embodiments, the one or more catalyst replacement components areintroduced continuously to the carbonylation reaction vessel at the samerate that the carbonylation reaction rate is observed to decrease. Insome embodiments, the one or more catalyst replacement components areintroduced intermittently to the carbonylation reaction vessel toproduce an average rate which matches the rate at which the which thecarbonylation reaction rate has been observed to decrease.

Thus if the carbonylation reaction rate has been observed to decrease 5%over the course of a time period, the catalyst replacement component mayeither be added continuously or intermittently at such a rate that 5% ofthe initial amount of Lewis acid or metal carbonyl present in thecarbonylation reaction vessel is added over that same time period. Insome embodiments, the catalyst replacement component is addedcontinuously. In some embodiments, the catalyst replacement component isadded every hour. In some embodiments, the catalyst replacementcomponent is added every 30 minutes. In some embodiments, the catalystreplacement component is added every 15 minutes. In some embodiments,the catalyst replacement component is added every 10 minutes. In someembodiments, the catalyst replacement component is added every 5minutes. In some embodiments, the catalyst replacement component isadded every minute.

One of skill in the art will appreciate that the shorter the intervalsat which the one or more catalyst replacement components are added, theless variation in the overall carbonylation reaction rate will beobserved. However this must be balanced against other considerationssuch as the complexity of making multiple additions and the effects ofnoise in data generated by the measurements used to determine theaddition rate.

V. Carbonylation Reaction Vessel and Catalyst Replacement Component FeedStreams

The methods herein place no particular limits on the type, size orgeometry of the reactor employed and indeed, in some cases, more thanone reactor may be employed. It is to be understood that the term“reactor” as recited in the methods herein may actually represent morethan one physical reactor (for example the reactor could be a train ofcontinuous stirred tank reactors (CSTRs) connected in parallel or inseries, or a plurality of plug flow reactors). In some embodiments, the“reactor” referred to in the methods herein may also comprise more thanone type of reactor (for example the reactor could comprise a CSTR inseries with a plug flow reactor).

Additional Processing Steps

In some embodiments, methods described herein comprise additional stepsto isolate the carbonylation product from the reaction product stream.These steps typically entail further treatment of the product streamfrom which the catalyst or catalyst component has been substantiallyremoved.

Thus, in some variations, the reacting of the epoxide or lactonefeedstock with the carbon monoxide in the presence of the carbonylationcatalyst in the carbonylation reaction vessel produces carbonylationproducts in a carbonylation product stream, and the methods describedherein further comprises separating the carbonylation product streamfrom the carbonylation reaction vessel. For example, the carbonylationproduct stream may be separated from the carbonylation reaction vesselby a nanofiltration membrane. The nanofiltration membrane may retain atleast a portion of the Lewis acid and the metal carbonyl, and permeatesthe carbonylation products. In some variations, the nanofiltrationmembrane is configured to retain solutes having a molecular weightgreater than the molecular weight of the epoxide or lactonecarbonylation products, and to allow solutes having lower molecularweights to permeate.

The precise mode of carrying out the carbonylation product isolation maydepend on the character of the carbonylation product. Suitable isolationmethods may include, for example, distillation, crystallization,precipitation, and evaporation. In embodiments where the carbonylationproduct is a liquid such as betapropiolactone or betabutyrolactone, themethods may further comprise performing distillation to separate thelactone from other components of the reaction product stream. Such othercomponents can include, for example, solvent(s), unreacted epoxide,reaction byproducts, and catalyst residues. In embodiments where thesolvent has a lower boiling point than the lactone, or where unreactedepoxide is present, the beta lactone may be retained as the bottoms inthe distillation with the solvent and/or epoxide taken to the vaporphase. In embodiments where the solvent has a boiling point higher thanthe lactone and/or where non volatile catalyst residues are present, thelactone may be taken to the vapor phase. In some embodiments, thecatalyst and/or unreacted epoxide are captured and fed back to theepoxide carbonylation reactor (either in real time, or via accumulationand use at a later time).

In embodiments where the carbonylation product is a solid such assuccinic anhydride or polypropiolactone, the methods may furthercomprise crystallization or precipitation to separate the carbonylationproduct from other components of the reaction product stream. Such othercomponents can include, for example, solvent(s), unreacted epoxide,reaction byproducts, and catalyst residues. In some embodiments, suchmethods include lowering the temperature of the reaction product stream.In some embodiments, such methods include removing solvent, excessepoxide and/or unreacted CO from the reaction product stream. In someembodiments, such methods comprise adding a solvent to the reactionproduct stream to cause precipitation or crystallization of thecarbonylation product.

In some embodiments, the methods described above may include additionalsteps intermediate between the carbonylation reaction and catalystseparation. In some embodiments, such steps include reduction of the COpressure. In some embodiments, the CO pressure is reduced to atmosphericpressure. In some embodiments, excess CO is removed by exposure tosub-atmospheric pressures or by sweeping with another gas. In someembodiments, the CO thus liberated is captured for re-use or isincinerated to provide heat. In some embodiments, the methods compriseheating or cooling the reaction product stream between the carbonylationreaction and catalyst separation. When methods include separation of asolid carbonylation product, they may include additional substeps suchas filtration, washing and collection of the solid product.

In certain embodiments, the carbonylation reaction vessel comprises oneor more continuous stirred tank reactors (CSTRs). In certainembodiments, the carbonylation reaction vessel comprises one or moreplug flow reactors. In certain embodiments, the carbonylation reactionvessel is also fed with an epoxide feed stream and carbon monoxide. Asused herein a catalyst replacement component being “added to thecarbonylation reaction vessel” contemplates any situation in which acatalyst replacement component is introduced to the carbonylationreaction vessel, including directly adding it to the carbonylationreaction vessel, or adding it at any point in the process before that.In some embodiments, a given catalyst replacement component is addedupstream from the carbonylation reaction vessel. In some embodiments, agiven catalyst replacement component is added directly to thecarbonylation reaction vessel. In some embodiments, a given catalystreplacement component is added to a feed stream of the reaction vessel(e.g. to the epoxide or carbon monoxide feed streams).

In certain embodiments where the one or more catalyst replacementcomponents are added to a carbonylation reaction vessel, the reactionvessel is also fed with an epoxide feed stream and carbon monoxide. Insome embodiments, a catalyst replacement component is added to theepoxide feed stream. In some embodiments, there is more than one epoxidefeed stream. In some embodiments, a catalyst replacement component isadded to at least one of the more than one epoxide feed streams. In someembodiments, a catalyst replacement component is added to one of themore than one epoxide feed streams, and one of the more than one epoxidefeed streams does not contain added catalyst replacement component.

In some such embodiments, each catalyst replacement component isintroduced to the reaction vessel in its own catalyst feed stream. Theintroduction of more than one catalyst replacement component, each inits own catalyst feed stream, is advantageous in a number of situations.One such situation is where the initial loading of the catalyst isformed in situ in the carbonylation reaction vessel from two catalystprecursors. Rather than remove the catalyst feed streams after theinitial loading, those feed streams remain connected and are used tosupplement the carbonylation reaction vessel with catalyst replacementcomponents. In some embodiments, the depletion of each component of thetwo-component catalyst does not occur at the same rate. Accordingly, insome embodiments, each catalyst replacement component should be added atdifferent times or at different rates, and multiple catalyst feedstreams are helpful for accomplishing this. In other embodiments,individual catalyst replacement components may not have compatiblephysical or chemical properties, and it is necessary to keep themseparate until they reach the carbonylation reaction vessel.

In some embodiments, a first catalyst replacement component is added tothe carbonylation reaction vessel in a first catalyst feed stream and asecond catalyst replacement component is added to the carbonylationreaction vessel in a second catalyst feed stream. In some embodimentsthe first catalyst feed stream and the second catalyst feed stream arefed to the carbonylation reaction vessel at rates such that a molarratio of epoxide to catalyst replacement component fed to the continuousreactor per unit time is between about 10 and about 200,000 moles ofepoxide per mole of the most rapidly added catalyst replacementcomponent. In certain embodiments, the molar ratio of epoxide to mostrapidly added catalyst replacement component fed to the reactor per unittime is between about 50 and about 50,000, between about 100 and about20,000, between about 100 and about 10,000, between about 100 and about5,000, or between about 100 and about 2,500. In certain embodiments, themolar ratio of epoxide to catalyst replacement component fed to thereactor per unit time is between about 100 and about 50,000, betweenabout 100 and about 20,000, between about 100 and about 10,000, betweenabout 100 and about 5,000, or between about 100 and about 2,500. Incertain embodiments, the molar ratio of epoxide to catalyst replacementcomponent fed to the reactor per unit time is between about 200 andabout 20,000, between about 500 and about 10,000, between about 500 andabout 5,000, between about 1,000 and about 5,000, between about 2,000and about 5,000 between about 2,000 and about 3,000, or between about5,000 and about 10,000. In certain embodiments, the molar ratio ofepoxide to catalyst replacement component fed to the reactor per unittime is between about 50,000 and about 200,000, between about 50,000 andabout 150,000, between about 50,000 and about 100,000, between about100,000 and about 200,000, between about 100,000 and about 150,000, orbetween about 150,000 and about 200,000.

In certain embodiments, each of the catalyst replacement componentfeedstreams comprises solvent. In certain embodiments, such feed streamscomprise an organic solvent selected from the group consisting of:aliphatic hydrocarbons, aromatic hydrocarbons, halogenated solvents,ethers, esters, ketones, nitriles, amides, carbonates, alcohols, amines,sulfones, or mixtures of any two or more of these. In certainembodiments, such feed streams comprise one or more ethers. In certainembodiments, an ether is selected from diethyl ether, methy-t-butylether, tetrahydrofuran, 1,4-dioxane, glyme, diglyme, triglyme, higherglymes, or mixtures of any two or more of these. In certain embodiments,such feed streams comprise 1,4-dioxane.

In certain embodiments, the first catalyst feed stream comprises ahomogenous solution of a Lewis acid or precursor to the Lewis acid in anorganic solvent. In certain embodiments, the first catalyst feed streamcomprises a slurry of a Lewis acid or a precursor to the Lewis acid inan organic solvent. In certain embodiments, the first catalyst feedstream comprises a neutral two-electron donor. In some embodiments, thefirst catalyst feed stream comprises an ether. In some embodiments, thefirst catalyst feed stream comprises tetrahydrofuran. In certainembodiments, the first catalyst feed stream comprises 1,4-dioxane.

In certain embodiments, the second catalyst feed stream comprises ahomogenous solution of a neutral metal carbonyl compound in an organicsolvent. In certain embodiments, the second catalyst feed streamcomprises a slurry of a neutral metal carbonyl compound in an organicsolvent. In certain embodiments, the second catalyst feed streamcomprises an ether. In certain embodiments, the second catalyst feedstream comprises tetrahydrofuran. In certain embodiments, the secondcatalyst feed stream comprises 1,4-dioxane.

In certain embodiments where at least one of the first or secondcarbonylation catalyst feed streams comprises an organic solvent, andwhere the epoxide carbonylation reaction is a continuous carbonylationprocess, the method is characterized in that there are no additionalsolvent feeds to the continuous reactor. Or put another way, the methodis characterized in that all of the reaction solvent fed to thecontinuous epoxide carbonylation reaction is provided via the catalystfeed streams.

As mentioned above, one advantage of methods described herein is theability to regenerate epoxide carbonylation catalysts that areessentially free of halide and/or alkali metal salt impurities.Therefore, in certain embodiments, provided are methods for feeding thecarbonylation reaction vessel of an epoxide carbonylation reaction withone or more catalyst replacement components characterized in that theepoxide carbonylation reaction vessel remains essentially free of halideand/or alkali metal salt impurities introduced with the catalystreplacement components. In certain embodiments, where a catalystreplacement component is introduced in the form of a salt, said salt isnot a halide or alkali metal salt. In certain embodiments, such methodsare characterized in that the epoxide carbonylation reaction vessel isessentially free of halide. In certain embodiments, the methods arecharacterized in that the epoxide carbonylation reaction vessel has ahalide content less than about 200 ppm. In certain embodiments, themethods are characterized in that the epoxide carbonylation reactionvessel has a halide content less than about 150 ppm, less than about 100ppm, less than about 50 ppm, less than about 40 ppm, less than about 30ppm, less than about 20 ppm, less than about 10 ppm, less than about 5ppm, less than about 2 ppm, or less than about 1 ppm. In certainembodiments, the methods are characterized in that the epoxidecarbonylation reaction vessel is essentially free of alkali metal salts.In certain embodiments, the methods are characterized in that theepoxide carbonylation reaction vessel has an alkali metal salt contentless than about 200 ppm. In certain embodiments, the methods arecharacterized in that the epoxide carbonylation reaction vessel has analkali metal salt content less than about 150 ppm, less than about 100ppm, less than about 50 ppm, less than about 40 ppm, less than about 30ppm, less than about 20 ppm, less than about 10 ppm, less than about 5ppm, less than about 2 ppm, or less than about 1 ppm.

In certain embodiments of methods for providing catalyst replacementcomponents to an epoxide carbonylation reaction, the neutral metalcarbonyl compound provided in the second catalyst feed stream has thegeneral formula Q′_(d)M_(e)(CO)_(w′), where each of Q′, M′, d, e, and w′is as defined above and in the classes and subclasses herein. In certainembodiments, the neutral metal carbonyl provided in the second catalystfeed stream has the general formula Q′M(CO)_(w′). In certainembodiments, the neutral metal carbonyl provided in the second catalystfeed stream has the general formula M(CO)_(w′). In certain embodiments,the neutral metal carbonyl provided in the second catalyst feed streamhas the general formula Q′M₂(CO)_(w′). In certain embodiments, theneutral metal carbonyl provided in the second catalyst feed stream hasthe general formula M₂(CO)_(w′). Suitable neutral metal carbonylcompounds include, for example, (CO)₇; V₂(CO)₁₂; Cr(CO)₆; Mo(CO)₆;W(CO)₆Mn₂(CO)₁₀; Tc₂(CO)₁₀; Re₂(CO)₁₀; Fe(CO)₅; Ru(CO)₅; Os(CO)₅;Ru₃(CO)₁₂; Os₃(CO)₁₂; Fe₃(CO)₁₂; Fe₂(CO)₉; Co₄(CO)₁₂; Rh₄(CO)₁₂;Rh₆(CO)₁₆; Ir₄(CO)₁₂; Co₂(CO)₈; and Ni(CO)₄.

In certain embodiments, the neutral metal carbonyl compound provided inthe second catalyst feed stream comprises a cobalt carbonyl compound. Incertain embodiments, the neutral metal carbonyl compound provided in thesecond catalyst feed stream is Co₂(CO)₈. In certain embodiments, theneutral metal carbonyl compound provided in the second catalyst feedstream is Co₄(CO)₁₂. In certain embodiments, the neutral metal carbonylcompound provided in the second catalyst feed stream is a mixture of twoor more cobalt carbonyl species.

In certain embodiments, the rate of addition of the first catalyst feedstream comprising the Lewis acid, or a precursor to the Lewis acid, andthe rate of addition of the second catalyst feed stream, comprising themetal carbonyl or a precursor to the metal carbonyl, are set such thatwithin the carbonylation reaction vessel, the molar ratio of metalcarbonyl, to Lewis acid is maintained at a ratio of about 1:1.

It should generally be understood that reference to “a first feedstream” and “a second feed stream”, etc., or “a first component” and “asecond components”, etc., does not necessarily imply an order of thefeed streams or components. In some variations, the use of suchreferences denotes the number of feed streams or components present. Inother variations, an order may be implied by the context in which thefeed streams or components are configured or used.

Carbonylation Reactions

Epoxide

In some variations, the methods herein involve the continuouscarbonylation of epoxides. The catalytic insertion of CO into epoxidesis known to yield several possible products the identity of which isinfluenced by the particular catalyst utilized and the reactionconditions employed. For example, in some variations, carbonylation canresult in the formation of a beta lactone as shown in the followinggeneral reaction:

Exemplary reactions include:

In other variations, carbonylation can result in the formation of apolyester as shown in the following general reaction:

Exemplary reactions include:

In yet other variations, carbonylation results in the formation of asuccinic anhydride by insertion of two molecules of CO. Such processesconform to the general reaction scheme:

Exemplary reactions include:

Any suitable epoxides may be used in the methods described herein. Noparticular constraints are placed on the identity of the epoxide used inthe carbonylation reactions described herein. In some embodiments, theepoxide is selected from the group consisting of ethylene oxide,propylene oxide, 1,2-butylene oxide, 2,3-butylene oxide,epichlorohydrin, cyclohexene oxide, cyclopentene oxide,3,3,3-Trifluoro-1,2-epoxypropane, styrene oxide, a glycidyl ether, and aglycidyl ester. In some embodiments, the epoxide is propylene oxide. Insome embodiments, the epoxide is ethylene oxide. In one variation whenthe epoxide is ethylene oxide, the carbonylation product is betapropriolactone. In another variation when the epoxide is ethylene oxide,the carbonylation product is succinic anhydride.

In some embodiments, the epoxide is ethylene oxide which is obtaineddirectly from the gas phase oxidation of ethylene. This embodiment isadvantageous in that it avoids the need to isolate, store, and transportethylene oxide which is both toxic and explosive. In some embodiments,the ethylene oxide is maintained in the gas phase as produced and fed tothe carbonylation reaction without condensing it to a liquid.

Lactones

In other variations, the methods herein involve the continuouscarbonylation of lactones. For example, in some variations,carbonylation of a beta lactone can result in the formation of asuccinic anhydride product, as shown in the following general reaction:

An example reaction includes:

In some embodiments, the lactone is beta propriolactone. In onevariation when the lactone is beta propriolactone, the carbonylationproduct is succinic anhydride.

Carbon Monoxide

Carbon monoxide (also referred to as “CO”) can be provided either as apure stream or as a mixture of carbon monoxide and one or moreadditional gases. In some embodiments, carbon monoxide is provided in amixture with hydrogen (e.g., Syngas). The ratio of carbon monoxide andhydrogen can be any ratio, including for example 1:1, 1:2, 1:4, 1:10,10:1, 4:1, or 2:1 or within any range with these ratios as end points.In some embodiments, the carbon monoxide is provided in mixture withgases as an industrial process gas. The carbon monoxide sources includefor example wood gas, producer gas, coal gas, town gas, manufacturedgas, hygas, Dowson gas or water gas, among others. In some embodiments,the carbon monoxide is provided at super-atmospheric pressure.

Feedstock Streams

In some embodiments, the feedstock stream fed into the carbonylationreaction comprises a gaseous mixture containing epoxide and carbonmonoxide. In some embodiments, the molar ratio of carbon monoxide toepoxide in the feedstock stream ranges from about 1:1 to about 10,000:1.In some embodiments, the molar ratio of carbon monoxide to epoxide inthe feedstock stream is about 5000:1, is about 2500:1, is about 2000:1,is about 1500:1, is about 1000:1, is about 500:1, is about 1:500, isabout 200:1, is about 100:1, is about 50:1, is about 20:1, is about10:1, is about 5:1 or is about 1:1. In some embodiments, the ratio ofcarbon monoxide to epoxide is selected, based on other reactionconditions, so that the reaction proceeds in an economical andtime-feasible manner. In some embodiments, the ratio of carbon monoxideto epoxide in the feedstock stream is between about 1:1 to about 100:1.In some embodiments, the ratio of carbon monoxide to epoxide in thefeedstock stream is between about 1:1 to about 1000:1. In someembodiments, the ratio of carbon monoxide to epoxide in the feedstockstream is between about 10:1 to about 1000:1. In some embodiments, theratio of carbon monoxide to epoxide in the feedstock stream is betweenabout 10:1 to about 10,000:1. In some embodiments, the ratio of carbonmonoxide to epoxide in the feedstock stream is between about 100:1 toabout 1000:1. In some embodiments, the ratio of carbon monoxide toepoxide in the feedstock stream is between about 10:1 to about 1000:1.In some embodiments, the ratio of carbon monoxide to epoxide in thefeedstock stream is between about 10:1 to about 500:1. In someembodiments, the ratio of carbon monoxide to epoxide in the feedstockstream is between about 10:1 to about 100:1. In some embodiments, theratio of carbon monoxide to epoxide in the feedstock stream is betweenabout 10:1 to about 50:1. In some embodiments, the ratio of carbonmonoxide to epoxide in the feedstock stream is between about 20:1 toabout 200:1. In some embodiments, the ratio of carbon monoxide toepoxide in the feedstock stream is between about 50:1 to about 200:1.

In some embodiments, the feedstock stream further comprises one or moreadditional components. In some embodiments, the additional componentscomprise diluents which do not directly participate in the chemicalreactions of the epoxide or the products of those reactions. In someembodiments, such diluents may include one or more inert gases (e.g.,nitrogen, argon, and helium) or volatile organic molecules such ashydrocarbons, and ethers. In some embodiments, the feedstock stream maycomprise hydrogen, traces of carbon dioxide, methane, and othercompounds commonly found in industrial carbon monoxide streams. In someembodiments, the feed stream may further comprise materials that mayhave a direct or indirect chemical function in one or more of theprocesses involved in the conversion of the epoxide to various endproducts. Additional reactants can also include mixtures of carbonmonoxide and another gas. For example, as noted above, in someembodiments, carbon monoxide is provided in a mixture with hydrogen(e.g., syngas).

In some embodiments, the feedstock stream is characterized in that it isessentially free of oxygen. In some embodiments, the feedstock stream ischaracterized in that it is essentially free of water. In someembodiments, the feedstock stream is characterized in that it isessentially free of oxygen and water.

Enumerated Embodiments

The following enumerated embodiments are representative of some aspectsof the invention.

1. A process for continuous carbonylation of an epoxide or lactonefeedstock, comprising:

reacting an epoxide or lactone feedstock with carbon monoxide in thepresence of a catalyst comprising a Lewis acid and a metal carbonyl in acarbonylation reaction vessel;

measuring one or more parameters selected from the group consisting of:

-   -   i) a concentration of the Lewis acid, or a decomposition product        thereof, within the carbonylation reaction vessel;    -   ii) a concentration of the Lewis acid, or a decomposition        product thereof, in a product stream downstream from the        carbonylation reaction vessel;    -   iii) a concentration of the metal carbonyl, or a decomposition        product thereof, within the carbonylation reaction vessel;    -   iv) a concentration of the metal carbonyl, or a decomposition        product thereof, in a product stream downstream from the        carbonylation reaction vessel; and    -   v) a rate of the carbonylation reaction;

comparing the measured value of the one or more parameters topredetermined reference values for the one or more parameters; and

where the measured value of any one of parameters i), iii), or v) isless than the reference value, or where the measured value of any one ofparameters ii) or iv) is greater than the reference value, introducingto the carbonylation reaction vessel a catalyst replacement componentwhich is different from the catalyst and comprises a species selectedfrom the group consisting of the Lewis acid, a precursor to the Lewisacid, the metal carbonyl, and a precursor to the metal carbonyl.

2. The process of embodiment 1, wherein the product stream is separatedfrom the carbonylation reaction vessel by a nanofiltration membrane.

3. The process of any one of the previous embodiments, wherein thenanofiltration membrane is designed to retain solutes having a molecularweight greater than the molecular weight of the epoxide or lactonecarbonylation products, and to allow solutes having lower molecularweights to permeate.4. The process of any one of the previous embodiments, wherein theprecursor to the metal carbonyl is a neutral metal carbonyl complex.5. The process of any one of the previous embodiments, wherein theprecursor to the metal carbonyl is Co₂(CO)₈ or Co₄(CO)₁₂.6. The process of any one of the previous embodiments, wherein theconcentration of the Lewis acid, or a decomposition product thereof, ismeasured by IR, UV, or NMR.7. The process of any one of the previous embodiments, wherein theconcentration of the metal carbonyl, or a decomposition product there ismeasured by IR, UV, or NMR.8. The process of any one of the previous embodiments, wherein thecatalyst replacement component is introduced directly to thecarbonylation reaction vessel.9. The process of any one of the previous embodiments, wherein thecatalyst replacement component is recycled from the product stream.10. The process of any one of the previous embodiments, wherein the oneor more parameters are measured continuously.11. The process of any one of the previous embodiments, wherein thecatalyst replacement component is added continuously.12. The process of any one of the previous embodiments, wherein thecatalyst replacement component is added intermittently.13. The process of any one of the previous embodiments, wherein theLewis acid is cationic.14. The process of any one of the previous embodiments, wherein themetal carbonyl is anionic.15. A process for continuous carbonylation of an epoxide or lactonefeedstock, the process comprising the steps of:

reacting an epoxide or lactone feedstock with carbon monoxide in thepresence of a catalyst comprising a Lewis acid and a metal carbonyl in acarbonylation reaction vessel; and

continuously or intermittently introducing to the carbonylation reactionvessel a catalyst replacement component which is different from thecatalyst and comprises a species selected from the group consisting ofthe Lewis acid, a precursor to the Lewis acid, the metal carbonyl, and aprecursor to the metal carbonyl.

16. The process of embodiment 15, wherein the catalyst replacementcomponent is introduced at a rate that results in less than 10%variation in the rate of the carbonylation reaction over a period of onehour.

17. The process of any one of the previous embodiments, wherein theLewis acid is of formula I:

wherein:

is a multidentate ligand;

M is a metal atom coordinated to the multidentate ligand; and

a is the charge of the metal atom and ranges from 0 to 2.

18. The process of any one of embodiments 1-16, wherein the Lewis acidis of formula II:

wherein:

M¹ is a first metal atom;

M² is a second metal atom;

each a is the charge of the metal atom and independently ranges from 0to 2; and

comprises a multidentate ligand system capable of coordinating bothmetal atoms.19. The process of embodiment 17, wherein the precursor to the Lewisacid is of the formula:

wherein:

is a multidentate ligand;

M is a metal atom coordinated to the multidentate ligand; and

R^(q) is selected from C₁₋₁₂ aliphatic and optionally substituted aryl.

20. The process of embodiment 18, wherein the precursor to the Lewisacid is of the formula:

wherein:

M¹ is a first metal atom;

M² is a second metal atom;

comprises a multidentate ligand system capable of coordinating bothmetal atoms; and

each R^(q) is independently selected from C₁₋₁₂ aliphatic and optionallysubstituted aryl.

21. A process for continuous carbonylation of an epoxide or lactonefeedstock, comprising:

continuously reacting an epoxide or lactone feedstock with carbonmonoxide in the presence of a carbonylation catalyst in a carbonylationreaction vessel,

-   -   wherein the carbonylation catalyst comprises a Lewis acid and a        metal carbonyl, and    -   wherein at a start time of the process, the carbonylation        reaction vessel contains an initial concentration of the Lewis        acid and an initial concentration of the metal carbonyl; and

adding to the carbonylation reaction vessel, at a time after the starttime of the process, a catalyst replacement component which is differentfrom the catalyst,

-   -   wherein the catalyst replacement component comprises the Lewis        acid, a precursor to the Lewis acid, the metal carbonyl, and a        precursor to the metal carbonyl.        22. The process of embodiment 21, wherein a rate or time of        addition of the catalyst replacement component is based on a        rate of depletion of one or both of the Lewis acid and the metal        carbonyl in the carbonylation reaction vessel.        23. The process of embodiment 22, wherein one or both of the        Lewis acid and the metal carbonyl of the carbonylation catalyst        depletes over time in the carbonylation reaction vessel, and the        method further comprises determining the depletion.        24. The process of embodiment 23, wherein the depletion of one        or both of the Lewis acid and the metal carbonyl in the        carbonylation reaction vessel is determined by:

measuring one or more parameters selected from the group consisting of:

-   -   i-a) a concentration of the Lewis acid in the carbonylation        reaction vessel;    -   i-b) a concentration of a decomposition product of the Lewis        acid in the carbonylation reaction vessel;    -   ii-a) a concentration of the Lewis acid in a process stream        downstream from the carbonylation reaction vessel;    -   ii-b) a concentration of a decomposition product of the Lewis        acid in a process stream downstream from the carbonylation        reaction vessel;    -   iii-a) a concentration of the metal carbonyl in the        carbonylation reaction vessel;    -   iii-b) a concentration of a decomposition product of the metal        carbonyl in the carbonylation reaction vessel;    -   iv-a) a concentration of the metal carbonyl in a process stream        downstream from the carbonylation reaction vessel;    -   iv-b) a concentration of a decomposition product of the metal        carbonyl in a process stream downstream from the carbonylation        reaction vessel; and    -   v) a rate of the carbonylation reaction; and

obtaining a measured value of the one or more parameters.

25. The process of embodiment 24, further comprising:

comparing the measured value of the one or more parameters to apredetermined reference value for each parameter; and

determining a rate of addition or a time of addition of the catalystreplacement component based on the comparison.

26. The process of embodiment 25, wherein the rate of addition of themetal carbonyl or a precursor to the metal carbonyl is increased whenthe value of a measurement in parameter iii-b, iv-a, or iv-b, or anycombination thereof, is greater than the predetermined value for eachparameter.27. The process of embodiment 25, wherein the rate of addition of themetal carbonyl or a precursor to the metal carbonyl is increased whenthe value of a measurement in parameter iii-a is less than thepredetermined value for the parameter.28. The process of embodiment 25, wherein the rate of addition of theLewis acid or a precursor to the Lewis Acid is increased when the valueof a measurement in parameter i-b, ii-a, or ii-b, or any combinationthereof, is greater than the predetermined value for each parameter.29. The process of embodiment 25, wherein the rate of addition of theLewis acid or a precursor to the Lewis acid is increased when the valueof a measurement in parameter i-a is less than the predetermined valuefor the parameter.30. The process of any one of embodiments 21 to 29, wherein the reactingof the epoxide or lactone feedstock with the carbon monoxide in thepresence of the carbonylation catalyst in the carbonylation reactionvessel produces carbonylation products in a carbonylation productstream, and

the process further comprises separating the carbonylation productstream from the carbonylation reaction vessel.

31. The process of embodiment 30, wherein the carbonylation productstream is separated from the carbonylation reaction vessel by ananofiltration membrane.

32. The process of embodiment 31, wherein the nanofiltration membraneretains at least a portion of the Lewis acid and the metal carbonyl, andpermeates the carbonylation products.

33. The process of any one of embodiments 21 to 32, wherein theprecursor to the metal carbonyl is a neutral metal carbonyl complex.

34. The process of any one of embodiments 21 to 33, wherein theprecursor to the metal carbonyl is Co₂(CO)₈ or Co₄(CO)₁₂.

35. The process of any one of embodiments 24 to 34, wherein theconcentration of the Lewis acid, or a decomposition product thereof, ismeasured by spectroscopy.

36. The process of any one of embodiments 24 to 35, wherein theconcentration of the Lewis acid, or a decomposition product thereof, ismeasured by IR, UV, mass or NMR spectroscopy.

37. The process of any one of embodiments 24 to 36, wherein theconcentration of the metal carbonyl, or a decomposition product thereof,is measured by spectroscopy.

38. The process of any one of embodiments 24 to 36, wherein theconcentration of the metal carbonyl, or a decomposition product thereof,is measured by IR, UV, mass or NMR spectroscopy.

39. The process of any one of embodiments 21 to 38, wherein the catalystreplacement component is added directly to the carbonylation reactionvessel.

40. The process of any one of embodiments 21 to 38, wherein the catalystreplacement component is recycled from a carbonylation product stream,an intermediate carbonylation process stream, or a process streamdownstream of the carbonylation reaction vessel.41. The process of any one of embodiments 24 to 40, wherein the one ormore parameters are measured continuously.42. The process of any one of embodiments 21 to 41, wherein the catalystreplacement component is added continuously.43. The process of any one of embodiments 21 to 41, wherein the catalystreplacement component is added intermittently.44. The process of any one of embodiments 21 to 43, wherein the Lewisacid is cationic.45. The process of any one of embodiments 21 to 44, wherein the metalcarbonyl is anionic.46. A process for continuous carbonylation of an epoxide or lactonefeedstock, comprising:

continuously reacting an epoxide or lactone feedstock with carbonmonoxide in the presence of a catalyst in a carbonylation reactionvessel, wherein the catalyst comprises a Lewis acid and a metalcarbonyl; and

continuously or intermittently introducing to the carbonylation reactionvessel a catalyst replacement component which is different from thecatalyst, wherein the catalyst replacement component comprises a speciesselected from the group consisting of the Lewis acid, a precursor to theLewis acid, the metal carbonyl, and a precursor to the metal carbonyl.

47. The process of embodiment 46, wherein the catalyst replacementcomponent is introduced at a rate that results in less than 10%variation in the rate of the carbonylation reaction over a period of onehour.

48. The process of any one of embodiments 21 to 47, wherein the Lewisacid is of formula I:

wherein:

is a multidentate ligand;

M is a metal atom coordinated to the multidentate ligand; and

a is the charge of the metal atom and ranges from 0 to 2.

49. The process of any one of embodiments 21 to 47, wherein the Lewisacid is of formula II:

wherein:

M¹ is a first metal atom;

M² is a second metal atom;

each a is the charge of the metal atom and independently ranges from 0to 2; and

comprises a multidentate ligand system capable of coordinating bothmetal atoms.50. The process of embodiment 48, wherein the precursor to the Lewisacid is of the formula:

wherein:

is a multidentate ligand;

M is a metal atom coordinated to the multidentate ligand; and

R^(q) is selected from C₁₋₁₂ aliphatic and optionally substituted aryl.

51. The process of embodiment 49, wherein the precursor to the Lewisacid is of the formula:

wherein:

M¹ is a first metal atom;

M² is a second metal atom;

comprises a multidentate ligand system capable of coordinating bothmetal atoms; and

each R^(q) is independently selected from C₁₋₁₂ aliphatic and optionallysubstituted aryl.

52. The process of any one of embodiments 21 to 51, wherein the epoxidefeedstock is continuously reacted with the carbon monoxide in thepresence of the carbonylation catalyst in the carbonylation reactionvessel.

53. The process of any one of embodiments 21 to 52, wherein the epoxidefeedstock comprises ethylene oxide.

54. The process of any one of embodiments 21 to 53, wherein continuouslyreacting the epoxide or lactone feedstock with the carbon monoxide inthe presence of the carbonylation catalyst produces beta-propiolactone.

55. The process of any one of embodiments 21 to 53, wherein continuouslyreacting the epoxide or lactone feedstock with the carbon monoxide inthe presence of the carbonylation catalyst produces succinic anhydride.

It is to be understood that the embodiments of the invention hereindescribed are merely illustrative of the application of the principlesof the invention. Reference herein to details of the illustratedembodiments is not intended to limit the scope of the claims, whichthemselves recite those features regarded as essential to the invention.

What is claimed is:
 1. A process for continuous carbonylation of an epoxide or lactone feedstock, comprising: continuously reacting an epoxide or lactone feedstock with carbon monoxide in the presence of a carbonylation catalyst in a carbonylation reaction vessel, wherein the carbonylation catalyst comprises a Lewis acid and a metal carbonyl, and wherein at a start time of the process, the carbonylation reaction vessel contains an initial concentration of the Lewis acid and an initial concentration of the metal carbonyl; and adding to the carbonylation reaction vessel, at a time after the start time of the process, a catalyst replacement component which is different from the carbonylation catalyst, wherein the catalyst replacement component comprises the Lewis acid, a precursor to the Lewis acid, the metal carbonyl, and a precursor to the metal carbonyl, wherein the precursor to the metal carbonyl is a neutral metal carbonyl complex, and wherein the precursor to the Lewis acid is:

wherein: each R^(q) is independently C₁₋₁₂ aliphatic or aryl, wherein the aryl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen; —(CH₂)₀₋₄R^(∘); —(CH₂)₀₋₄OR^(∘); —O—(CH₂)₀₋₄C(O)OR^(∘); —(CH₂)₀₋₄CH(OR^(∘))₂; —(CH₂)₀₋₄SR^(∘); —(CH₂)₀₋₄Ph; —(CH₂)₀₋₄O(CH₂)₀₋₁Ph; —CH═CHPh; —NO₂; —CN; —N₃; —(CH₂)₀₋₄N(R^(∘))₂; —(CH₂)₀₋₄N(R^(∘)C(O)R^(∘); —N(R^(∘)C(S)R^(∘); —(CH₂)₀₋₄N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))C(S)NR^(∘) ₂; —(CH₂)₀₋₄N(R^(∘))C(O)OR^(∘); —N(R^(∘))N(R^(∘))C(O)R^(∘); —N(R^(∘))N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))N(R^(∘))C(O)OR^(∘); —(CH₂)₀₋₄C(O)R^(∘); —C(S)R^(∘); —(CH₂)₀₋₄C(O)OR^(∘); —(CH₂)₀₋₄C(O)N(R^(∘))₂; —(CH₂)₀₋₄C(O)SR^(∘); —(CH₂)₀₋₄C(O)OSiR^(∘) ₃; —(CH₂)₀₋₄OC(O)R^(∘); —OC(O)(CH₂)₀₋₄SR^(∘); —SC(S)SR^(∘); —(CH₂)₀₋₄SC(O)R^(∘); —(CH₂)₀₋₄C(O)NR^(∘) ₂; —C(S)NR^(∘) ₂; —C(S)SR^(∘), —SC(S)SR^(∘); —(CH₂)₀₋₄OC(O)NR^(∘) ₂; —C(O)N(OR^(∘))R^(∘), —C(O)C(O)R^(∘), —C(O)CH₂C(O)R^(∘); —C(NOR^(∘))R^(∘); —(CH₂)₀₋₄SSR^(∘); —(CH₂)₀₋₄S(O)₂R^(∘); —(CH₂)₀₋₄S(O)₂OR^(∘); —(CH₂)₀₋₄OS(O)₂R^(∘); —S(O)₂NR^(∘) ₂; —(CH₂)₀₋₄S(O)R^(∘); —N(R^(∘))S(O)₂NR^(∘) ₂; —N(R^(∘))S(O)₂R^(∘); —N(OR^(∘))R^(∘); —C(NH)NR^(∘) ₂; —P(O)₂R^(∘); —P(O)R^(∘) ₂; —OP(O)R^(∘) ₂; —OP(O)(OR^(∘))₂; SiR^(∘) ₃; —(C₁₋₄ straight or branched alkylene)O—N(R^(∘))₂; and —(C₁₋₄ straight or branched alkylene)C(O)O—N(R^(∘))₂, wherein R^(∘)at each occurrence is independently hydrogen, C₁₋₈ aliphatic, —CH₂Ph, or —O(CH₂)₀₋₁Ph; or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or wherein two independent occurrences of R^(∘), taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or polycyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; M is a metal atom; R^(d) at each occurrence is independently hydrogen, halogen, —OR⁴, —NR^(y) ₂, —SR^(y), —CN, —NO₂, —SO₂R^(y), —SOR^(y), —SO₂NR^(y) ₂; —CNO, —NR^(y)SO₂R^(y), —NCO, —N₃, or —SiR^(y) ₃; or an optionally substituted group selected from the group consisting of: C₁₋₂₀ aliphatic; C₁₋₂₀ heteroaliphatic having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; 6- to 10-membered aryl; 5- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 4- to 7-membered heterocyclic having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; or wherein two or more R^(d) groups may be taken together to form one or more optionally substituted rings; each R^(y) is independently hydrogen; or an optionally substituted group selected the group consisting of: acyl; carbamoyl, arylalkyl; 6- to 10-membered aryl; C₁₋₁₂ aliphatic; C₁₋₁₂ heteroaliphatic having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; 5- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; 4- to 7-membered heterocyclic having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; an oxygen protecting group; and a nitrogen protecting group; or wherein two R^(y) on the same nitrogen atom are taken with the nitrogen atom to form an optionally substituted 4- to 7-membered heterocyclic ring having 0-2 additional heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and each R⁴ is independently a hydroxyl protecting group or R^(y); R^(1a), R^(1a′), R^(2a), R^(2a′), R^(3a), and R^(3a′) are independently hydrogen, halogen, —OR⁴, —NR^(y) ₂, —SR^(y), —CN, —NO₂, —SO₂R^(y), —SOR^(y), —SO₂NR^(y) ₂; —CNO, —NR^(y)SO₂R^(y), —NCO, —N₃, or —SiR^(y) ₃; or an optionally substituted group selected from the group consisting of: C₁₋₂₀ aliphatic; C₁₋₂₀ heteroaliphatic having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; 6- to 10-membered aryl; 5- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 4- to 7-membered heterocyclic having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; or wherein any of (R^(2a′) and R^(3′)), (R^(2a) and R^(3a)), (R^(1a) and R^(2a)), and (R^(1a′) and R^(2′)) may optionally be taken together with the carbon atoms to which they are attached to form one or more rings which may in turn be substituted with one or more R^(y) groups; and R^(4a) is selected from the group consisting of:

wherein: R^(c) at each occurrence is independently hydrogen, halogen, —OR⁴, —NR^(y) ₂, —SR^(y), —CN, —NO₂, —SO₂R^(y), —SOR^(y), —SO₂NR^(y) ₂; —CNO, —NR^(y)SO₂R^(y), —NCO, —N₃, or —SiR^(y) ₃; or an optionally substituted group selected from the group consisting of:  C₁₋₂₀ aliphatic;  C₁₋₂₀ heteroaliphatic having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;  6- to 10-membered aryl;  5- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and  4- to 7-membered heterocyclic having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; or wherein two or more R^(c) groups may be taken together with the carbon atoms to which they are attached and any intervening atoms to form one or more rings; or wherein two R^(c) groups are attached to the same carbon atom, they may be taken together along with the carbon atom to which they are attached to form a moiety selected from the group consisting of: a 3- to 8-membered spirocyclic ring, a carbonyl, an oxime, a hydrazone, an imine; and an optionally substituted alkene; Y is a divalent linker selected from the group consisting of: —NR^(y)—, —N(R^(y))C(O)—, —C(O)NR^(y)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO₂—, —C(═S)—, —C(═NR^(y))—, —N═N—; a polyether; a C₃ to C₈ substituted or unsubstituted carbocycle; and a C₁ to C₈ substituted or unsubstituted heterocycle; m′ is 0 or an integer from 1 to 4, inclusive; and q is 0 or an integer from 1 to 4, inclusive.
 2. The process of claim 1, wherein a rate or time of addition of the catalyst replacement component is based on a rate of depletion of one or both of the Lewis acid and the metal carbonyl in the carbonylation reaction vessel.
 3. The process of claim 2, wherein one or both of the Lewis acid and the metal carbonyl of the carbonylation catalyst depletes over time in the carbonylation reaction vessel, and the method further comprises determining the depletion, wherein the depletion of one or both of the Lewis acid and the metal carbonyl in the carbonylation reaction vessel is determined by: measuring one or more parameters selected from the group consisting of: i-a) a concentration of the Lewis acid in the carbonylation reaction vessel; i-b) a concentration of a decomposition product of the Lewis acid in the carbonylation reaction vessel; ii-a) a concentration of the Lewis acid in a process stream downstream from the carbonylation reaction vessel; ii-b) a concentration of a decomposition product of the Lewis acid in a process stream downstream from the carbonylation reaction vessel; iii-a) a concentration of the metal carbonyl in the carbonylation reaction vessel; iii-b) a concentration of a decomposition product of the metal carbonyl in the carbonylation reaction vessel; iv-a) a concentration of the metal carbonyl in a process stream downstream from the carbonylation reaction vessel; iv-b) a concentration of a decomposition product of the metal carbonyl in a process stream downstream from the carbonylation reaction vessel; and v) a rate of the carbonylation reaction; and obtaining a measured value of the one or more parameters.
 4. The process of claim 3, further comprising: comparing the measured value of the one or more parameters to a predetermined reference value for each parameter; and determining a rate of addition or a time of addition of the catalyst replacement component based on the comparison.
 5. The process of claim 4, wherein: the rate of addition of the metal carbonyl or a precursor to the metal carbonyl is increased when the value of a measurement in parameter iii-b, iv-a, or iv-b, or any combination thereof, is greater than the predetermined value for each parameter; the rate of addition of the metal carbonyl or a precursor to the metal carbonyl is increased when the value of a measurement in parameter iii-a is less than the predetermined value for the parameter; the rate of addition of the Lewis acid or a precursor to the Lewis Acid is increased when the value of a measurement in parameter i-b, ii-a, or ii-b, or any combination thereof, is greater than the predetermined value for each parameter; and the rate of addition of the Lewis acid or a precursor to the Lewis acid is increased when the value of a measurement in parameter i-a is less than the predetermined value for the parameter.
 6. The process of claim 1, wherein the reacting of the epoxide or lactone feedstock with the carbon monoxide in the presence of the carbonylation catalyst in the carbonylation reaction vessel produces carbonylation products in a carbonylation product stream, and the process further comprises separating the carbonylation product stream from the carbonylation reaction vessel.
 7. The process of claim 6, wherein the carbonylation product stream is separated from the carbonylation reaction vessel by a nanofiltration membrane, and wherein the nanofiltration membrane retains at least a portion of the Lewis acid and the metal carbonyl, and permeates the carbonylation products.
 8. The process of claim 1, wherein the precursor to the metal carbonyl is Co₂(CO)₈ or Co₄(CO)₁₂.
 9. The process of claim 1, wherein the catalyst replacement component is added directly to the carbonylation reaction vessel.
 10. The process of claim 1, wherein the catalyst replacement component is recycled from a carbonylation product stream, an intermediate carbonylation process stream, or a process stream downstream of the carbonylation reaction vessel.
 11. The process of claim 3, wherein the one or more parameters are measured continuously.
 12. The process of claim 1, wherein the catalyst replacement component is added continuously.
 13. The process of claim 1, wherein the catalyst replacement component is added intermittently.
 14. A process for continuous carbonylation of an epoxide or lactone feedstock, comprising: continuously reacting an epoxide or lactone feedstock with carbon monoxide in the presence of a catalyst in a carbonylation reaction vessel, wherein the catalyst comprises a Lewis acid and a metal carbonyl; and continuously or intermittently introducing to the carbonylation reaction vessel a catalyst replacement component which is different from the carbonylation catalyst, wherein the catalyst replacement component comprises a species selected from the group consisting of the Lewis acid, a precursor to the Lewis acid, the metal carbonyl, and a precursor to the metal carbonyl, wherein the precursor to the metal carbonyl is a neutral metal carbonyl complex, and wherein the precursor to the Lewis acid is:

wherein: each R^(q) is independently C₁₋₁₂ aliphatic or aryl, wherein the aryl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen; —(CH₂)₀₋₄R^(∘); —(CH₂)₀₋₄OR^(∘); —O—(CH₂)₀₋₄C(O)OR^(∘); —(CH₂)₀₋₄ CH(OR^(∘))₂; —(CH₂)₀₋₄SR^(∘); —(CH₂)₀₋₄Ph; —(CH₂)₀₋₄O(CH₂)₀₋₁Ph; —CH═CHPh; —NO₂; —CN; —N₃; —(CH₂)₀₋₄N(R^(∘))₂; —(CH₂)₀₋₄N(R^(∘)C(O)R^(∘); —N(R^(∘)C(S)R^(∘); —(CH₂)₀₋₄N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))C(S)NR^(∘) ₂; —(CH₂)₀₋₄N(R^(∘))C(O)OR^(∘); —N(R^(∘))N(R^(∘))C(O)R^(∘); —N(R^(∘))N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))N(R^(∘))C(O)OR^(∘); —(CH₂)₀₋₄C(O)R^(∘); —C(S)R^(∘); —(CH₂)₀₋₄C(O)OR^(∘); —(CH₂)₀₋₄C(O)N(R^(∘))₂; —(CH₂)₀₋₄C(O)SR^(∘); —(CH₂)₀₋₄C(O)OSiR^(∘) ₃; —(CH₂)₀₋₄OC(O)R^(∘); —OC(O)(CH₂)₀₋₄SR^(∘); —SC(S)SR^(∘); —(CH₂)₀₋₄SC(O)R^(∘); —(CH₂)₀₋₄C(O)NR^(∘) ₂; —C(S)NR^(∘) ₂; —C(S)SR^(∘), —SC(S)SR^(∘); —(CH₂)₀₋₄OC(O)NR^(∘) ₂; —C(O)N(OR^(∘))R^(∘), —C(O)C(O)R^(∘), —C(O)CH₂C(O)R^(∘); —C(NOR^(∘))R^(∘); —(CH₂)₀₋₄SSR^(∘); —(CH₂)₀₋₄S(O)₂R^(∘); —(CH₂)₀₋₄S(O)₂OR^(∘); —(CH₂)₀₋₄OS(O)₂R^(∘); —S(O)₂NR^(∘) ₂; —(CH₂)₀₋₄S(O)R^(∘); —N(R^(∘))S(O)₂NR^(∘) ₂; —N(R^(∘))S(O)₂R^(∘); —N(OR^(∘))R^(∘); —C(NH)NR^(∘) ₂; —P(O)₂R^(∘); —P(O)R^(∘) ₂; —OP(O)R^(∘) ₂; —OP(O)(OR^(∘))₂; SiR^(∘) ₃; —(C₁₋₄ straight or branched alkylene)O—N(R^(∘))₂; and —(C₁₋₄ straight or branched alkylene)C(O)O—N(R^(∘))₂, wherein R^(∘)at each occurrence is independently hydrogen, C₁₋₈ aliphatic, —CH₂Ph or —O(CH₂)₀₋₁Ph; or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or wherein two independent occurrences of R^(∘), taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or polycyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; M is a metal atom; R^(d) at each occurrence is independently hydrogen, halogen, —OR⁴, —NR^(y) ₂, —SR^(y), —CN, —NO₂, —SO₂R^(y), —SOR^(y), —SO₂NR^(y) ₂; —CNO, —NR^(y)SO₂R^(y), —NCO, —N₃, or —SiR^(y) ₃; or an optionally substituted group selected from the group consisting of: C₁₋₂₀ aliphatic; C₁₋₂₀ heteroaliphatic having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; 6- to 10-membered aryl; 5- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 4- to 7-membered heterocyclic having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; or wherein two or more R^(d) groups may be taken together to form one or more optionally substituted rings; each R^(y) is independently hydrogen; or an optionally substituted group selected the group consisting of: acyl; carbamoyl, arylalkyl; 6- to 10-membered aryl; C₁₋₁₂ aliphatic; C₁₋₁₂ heteroaliphatic having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; 5- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; 4- to 7-membered heterocyclic having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; an oxygen protecting group; and a nitrogen protecting group; or wherein two R^(y) on the same nitrogen atom are taken with the nitrogen atom to form an optionally substituted 4- to 7-membered heterocyclic ring having 0-2 additional heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and each R⁴ is independently a hydroxyl protecting group or R^(y); R^(1a), R^(1a′), R^(2a), R^(2a′), R^(3a), and R^(3a′) are independently hydrogen, halogen, —OR⁴, —NR^(y) ₂, —SR^(y), —CN, —NO₂, —SO₂R^(y), —SOR^(y), —SO₂NR^(y) ₂; —CNO, —NR^(y)SO₂R^(y), —NCO, —N₃, or —SiR^(y) ₃; or an optionally substituted group selected from the group consisting of: C₁₋₂₀ aliphatic; C₁₋₂₀ heteroaliphatic having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; 6- to 10-membered aryl; 5- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 4- to 7-membered heterocyclic having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; or wherein any of (R^(2a′) and R^(3′)), (R^(2a) and R^(3a)), (R^(1a) and R^(2a)), and (R^(1a′) and R^(2′)) may optionally be taken together with the carbon atoms to which they are attached to form one or more rings which may in turn be substituted with one or more R^(y) groups; and R^(4a) is selected from the group consisting of:

wherein: R^(c) at each occurrence is independently hydrogen, halogen, —OR⁴, —NR^(y) ₂, —SR^(y), —CN, —NO₂, —SO₂R^(y), —SOR^(y), —SO₂NR^(y) ₂; —CNO, —NR^(y)SO₂R^(y), —NCO, —N₃, or —SiR^(y) ₃; or an optionally substituted group selected from the group consisting of:  C₁₋₂₀ aliphatic;  C₁₋₂₀ heteroaliphatic having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;  6- to 10-membered aryl;  5- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and  4- to 7-membered heterocyclic having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; or wherein two or more R^(c) groups may be taken together with the carbon atoms to which they are attached and any intervening atoms to form one or more rings; or wherein two R^(c) groups are attached to the same carbon atom, they may be taken together along with the carbon atom to which they are attached to form a moiety selected from the group consisting of: a 3- to 8-membered spirocyclic ring, a carbonyl, an oxime, a hydrazone, an imine; and an optionally substituted alkene; Y is a divalent linker selected from the group consisting of: —NR^(y)—, —N(R^(y))C(O)—, —C(O)NR^(y)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO₂—, —C(═S)—, —C(═NR^(y))—, —N═N—; a polyether; a C₃ to C₈ substituted or unsubstituted carbocycle; and a C₁ to C₈ substituted or unsubstituted heterocycle; m′ is 0 or an integer from 1 to 4, inclusive; and q is 0 or an integer from 1 to 4, inclusive.
 15. The process of claim 14, wherein the catalyst replacement component is introduced at a rate that results in less than 10% variation in the rate of the carbonylation reaction over a period of one hour.
 16. The process of claim 1, wherein the epoxide feedstock is continuously reacted with the carbon monoxide in the presence of the carbonylation catalyst in the carbonylation reaction vessel.
 17. The process of claim 1, wherein the epoxide feedstock comprises ethylene oxide.
 18. The process of claim 1, wherein the precursor to the Lewis acid is


19. The process of claim 1, wherein the precursor to the Lewis acid is


20. The process of claim 1, wherein the precursor to the Lewis acid is


21. The process of claim 1, wherein the precursor to the Lewis acid is


22. The process of claim 1, wherein the precursor to the Lewis acid is


23. The process of claim 1, wherein the precursor to the Lewis acid is


24. The process of claim 1, wherein the precursor to the Lewis acid is


25. The process of claim 1, wherein M is aluminum, chromium, titanium, indium, gallium, zinc, cobalt, or copper.
 26. The process of claim 1, wherein M is aluminum or chromium.
 27. The process of claim 1, wherein the catalyst replacement components have a halide content less than about 200 ppm.
 28. A process for continuous carbonylation of an epoxide or lactone feedstock, comprising: continuously reacting an epoxide or lactone feedstock with carbon monoxide in the presence of a carbonylation catalyst in a carbonylation reaction vessel to produce a carbonylation product stream, wherein the carbonylation catalyst comprises a Lewis acid and a metal carbonyl, wherein the carbonylation product stream comprises at least one carbonylation product, at least some of the Lewis acid and at least some of the metal carbonyl, and wherein at a start time of the process, the carbonylation reaction vessel contains an initial concentration of the Lewis acid and an initial concentration of the metal carbonyl; separating the carbonylation product stream from the carbonylation reaction vessel by a nanofiltration membrane, wherein the nanofiltration membrane retains at least a portion of the Lewis acid and at least a portion of the metal carbonyl, and permeates at least one carbonylation product; and adding to the carbonylation reaction vessel, at a time after the start time of the process, a catalyst replacement component which is different from the carbonylation catalyst, wherein the catalyst replacement component is added at a rate or time of addition based on a rate of depletion of one or both of the Lewis acid and the metal carbonyl in the carbonylation reaction vessel, wherein the catalyst replacement component comprises the Lewis acid, a precursor to the Lewis acid, the metal carbonyl, and a precursor to the metal carbonyl, wherein the precursor to the metal carbonyl is a neutral metal carbonyl complex, and wherein the precursor to the Lewis acid is:

wherein: each R^(q) is independently C₁₋₁₂ aliphatic or aryl, wherein the aryl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen; —(CH₂)₀₋₄R^(∘); —(CH₂)₀₋₄OR^(∘); —O—(CH₂)₀₋₄C(O)OR^(∘); —(CH₂)₀₋₄ CH(OR^(∘))₂; —(CH₂)₀₋₄SR^(∘); —(CH₂)₀₋₄Ph; —(CH₂)₀₋₄O(CH₂)₀₋₁Ph; —CH═CHPh; —NO₂; —CN; —N₃; —(CH₂)₀₋₄N(R^(∘))₂; —(CH₂)₀₋₄N(R^(∘)C(O)R^(∘); —N(R^(∘)C(S)R^(∘); —(CH₂)₀₋₄N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))C(S)NR^(∘) ₂; —(CH₂)₀₋₄N(R^(∘))C(O)OR^(∘); —N(R^(∘))N(R^(∘))C(O)R^(∘); —N(R^(∘))N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))N(R^(∘))C(O)OR^(∘); —(CH₂)₀₋₄C(O)R^(∘); —C(S)R^(∘); —(CH₂)₀₋₄C(O)OR^(∘); —(CH₂)₀₋₄C(O)N(R^(∘))₂; —(CH₂)₀₋₄C(O)SR^(∘); —(CH₂)₀₋₄C(O)OSiR^(∘) ₃; —(CH₂)₀₋₄OC(O)R^(∘); —OC(O)(CH₂)₀₋₄SR^(∘); —SC(S)SR^(∘); —(CH₂)₀₋₄SC(O)R^(∘); —(CH₂)₀₋₄C(O)NR^(∘) ₂; —C(S)NR^(∘) ₂; —C(S)SR^(∘), —SC(S)SR^(∘); —(CH₂)₀₋₄OC(O)NR^(∘) ₂; —C(O)N(OR^(∘))R^(∘), —C(O)C(O)R^(∘), —C(O)CH₂C(O)R^(∘); —C(NOR^(∘))R^(∘); —(CH₂)₀₋₄SSR^(∘); —(CH₂)₀₋₄S(O)₂R^(∘); —(CH₂)₀₋₄S(O)₂OR^(∘); —(CH₂)₀₋₄OS(O)₂R^(∘); —S(O)₂NR^(∘) ₂; —(CH₂)₀₋₄S(O)R^(∘); —N(R^(∘))S(O)₂NR^(∘) ₂; —N(R^(∘))S(O)₂R^(∘); —N(OR^(∘))R^(∘); —C(NH)NR^(∘) ₂; —P(O)₂R^(∘); —P(O)R^(∘) ₂; —OP(O)R^(∘) ₂; —OP(O)(OR^(∘))₂; SiR^(∘) ₃; —(C₁₋₄ straight or branched alkylene)O—N(R^(∘))₂; and —(C₁₋₄ straight or branched alkylene)C(O)O—N(R^(∘))₂, wherein R^(∘)at each occurrence is independently hydrogen, C₁₋₈ aliphatic, —CH₂Ph, or —O(CH₂)₀₋₁Ph; or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or wherein two independent occurrences of R^(∘), taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or polycyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; M is a metal atom; R^(d) at each occurrence is independently hydrogen, halogen, —OR⁴, —NR^(y) ₂, —SR^(y), —CN, —NO₂, —SO₂R^(y), —SOR^(y), —SO₂NR^(y) ₂; —CNO, —NR^(y)SO₂R^(y), —NCO, —N₃, or —SiR^(y) ₃; or an optionally substituted group selected from the group consisting of: C₁₋₂₀ aliphatic; C₁₋₂₀ heteroaliphatic having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; 6- to 10-membered aryl; 5- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 4- to 7-membered heterocyclic having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; or wherein two or more R^(d) groups may be taken together to form one or more optionally substituted rings; each R^(y) is independently hydrogen; or an optionally substituted group selected the group consisting of: acyl; carbamoyl, arylalkyl; 6- to 10-membered aryl; C₁₋₁₂ aliphatic; C₁₋₁₂ heteroaliphatic having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; 5- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; 4- to 7-membered heterocyclic having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; an oxygen protecting group; and a nitrogen protecting group; or wherein two R^(y) on the same nitrogen atom are taken with the nitrogen atom to form an optionally substituted 4- to 7-membered heterocyclic ring having 0-2 additional heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and each R⁴ is independently a hydroxyl protecting group or R^(y); R^(1a), R^(1a′), R^(2a), R^(2a′), R^(3a), and R^(3a′) are independently hydrogen, halogen, —OR⁴, —NR^(y) ₂, —SR^(y), —CN, —NO₂, —SO₂R^(y), —SOR^(y), —SO₂NR^(y) ₂; —CNO, —NR^(y)SO₂R^(y), —NCO, —N₃, or —SiR^(y) ₃; or an optionally substituted group selected from the group consisting of: C₁₋₂₀ aliphatic; C₁₋₂₀ heteroaliphatic having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; 6- to 10-membered aryl; 5- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 4- to 7-membered heterocyclic having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; or wherein any of (R^(2a′) and R^(3′)), (R^(2a) and R^(3a)), (R^(1a) and R^(2a)), and (R^(1a′) and R^(2′)) may optionally be taken together with the carbon atoms to which they are attached to form one or more rings which may in turn be substituted with one or more R^(y) groups; and R^(4a) is selected from the group consisting of:

wherein: R^(c) at each occurrence is independently hydrogen, halogen, —OR⁴, —NR^(y) ₂, —SR^(y), —CN, —NO₂, —SO₂R^(y), —SOR^(y), —SO₂NR^(y) ₂; —CNO, —NR^(y)SO₂R^(y), —NCO, —N₃, or —SiR^(y) ₃; or an optionally substituted group selected from the group consisting of:  C₁₋₂₀ aliphatic;  C₁₋₂₀ heteroaliphatic having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;  6- to 10-membered aryl;  5- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and  4- to 7-membered heterocyclic having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; or wherein two or more R^(c) groups may be taken together with the carbon atoms to which they are attached and any intervening atoms to form one or more rings; or wherein two R^(c) groups are attached to the same carbon atom, they may be taken together along with the carbon atom to which they are attached to form a moiety selected from the group consisting of: a 3- to 8-membered spirocyclic ring, a carbonyl, an oxime, a hydrazone, an imine; and an optionally substituted alkene; Y is a divalent linker selected from the group consisting of: —NR^(y)—, —N(R^(y))C(O)—, —C(O)NR^(y)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO₂—, —C(═S)—, —C(═NR^(y))—, —N═N—; a polyether; a C₃ to C₈ substituted or unsubstituted carbocycle; and a C₁ to C₈ substituted or unsubstituted heterocycle; m′ is 0 or an integer from 1 to 4, inclusive; and q is 0 or an integer from 1 to 4, inclusive.
 29. The process of claim 1, wherein each R^(q) is independently C₁₋₁₂ aliphatic.
 30. The process of claim 14, wherein each R^(q) is independently C₁₋₁₂ aliphatic.
 31. The process of claim 28, wherein each R^(q) is independently C₁₋₁₂ aliphatic. 